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Ollagnon M, Bresson-Hadni S, Spahr L, Rubbia-Brandt L, Toso C, Chappuis F. Alveolar echinococcosis in the canton of Geneva between 2010 and 2021: a descriptive analysis. Swiss Med Wkly 2025; 155:3863. [PMID: 39977361 DOI: 10.57187/s.3863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND Alveolar echinococcosis is a rare but potentially severe parasitic disease caused by the larval stage of Echinococcus multilocularis, endemic in many countries in the northern hemisphere, including Switzerland. While the liver is most commonly affected, other organs can also be involved either by contiguity or haematogenous spread. To date, there is no epidemiological or clinical data on alveolar echinococcosis in the canton of Geneva. OBJECTIVES To describe the demographic, epidemiological, clinical and therapeutic characteristics of alveolar echinococcosis in the canton of Geneva between 2010 and 2021. METHODS An investigation was conducted among physicians from Geneva University Hospitals (HUG) and the private sector likely to encounter patients diagnosed with alveolar echinococcosis between 2010 and 2021. All patients being treated in the canton of Geneva were included. After obtaining their consent, an epidemiological questionnaire was completed by patients, and a clinical questionnaire by their referring physicians. Demographic, epidemiological and clinical data were entered into REDCap, then extracted and analysed. RESULTS Of a total of 27 patients diagnosed with alveolar echinococcosis, 25 were included in the study; one patient did not provide his consent and one patient could not be contacted. The annual incidence of alveolar echinococcosis in the canton of Geneva was calculated at 0.24 cases per 100,000 inhabitants based on the subset (n = 14) domiciled in Geneva. The vast majority of patients (n = 24; 96%) were followed at HUG. The median age of patients was 55 years (range: 17-79) with a slight predominance of women (56%). Reported risk factors for alveolar echinococcosis included owning a vegetable garden (70.8%), often unfenced, practicing composting (69.6%), and owning a dog (58.3%) or a cat (58.3%). Four patients (16%) had an immunosuppressive condition. Only 52% of patients were symptomatic at the time of diagnosis. The liver was affected in most cases (n = 24; 96%), but one patient had a primary splenic location. Surgical resection for curative purposes was performed in 13 patients (52%). All patients received parasitostatic treatment with albendazole, discontinued in 5 patients (20%) due to drug-induced hepatitis. Three patients died (12%), of which two directly related to alveolar echinococcosis. CONCLUSION Alveolar echinococcosis, a rare but severe disease, is endemic in the canton of Geneva. The establishment of mandatory reporting of this disease in Switzerland would allow monitoring of its epidemiological evolution. Primary and secondary prevention measures, currently non-existent, could potentially lower the incidence and severity of the disease.
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Affiliation(s)
- Manon Ollagnon
- Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Solange Bresson-Hadni
- Division of Tropical and Humanitarian Medicine, University Hospitals of Geneva, Geneva, Switzerland
- Division of Gastroenterology and Hepatology, University Hospitals of Geneva, Geneva, Switzerland
| | - Laurent Spahr
- Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Division of Gastroenterology and Hepatology, University Hospitals of Geneva, Geneva, Switzerland
| | - Laura Rubbia-Brandt
- Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Division of Clinical Pathology, University Hospitals of Geneva, Geneva, Switzerland
| | - Christian Toso
- Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Division of Visceral Surgery, University Hospitals of Geneva, Geneva, Switzerland
| | - François Chappuis
- Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Division of Tropical and Humanitarian Medicine, University Hospitals of Geneva, Geneva, Switzerland
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Zhu J, Zhao H, Aierken A, Zhou T, Menggen M, Gao H, He R, Aimulajiang K, Wen H. Ghrelin is involved in regulating the progression of Echinococcus Granulosus-infected liver lesions through suppression of immunoinflammation and fibrosis. PLoS Negl Trop Dis 2024; 18:e0012587. [PMID: 39436864 PMCID: PMC11495594 DOI: 10.1371/journal.pntd.0012587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 09/30/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND Cystic Echinococcosis (CE) is a zoonotic disease causing fibrosis and necrosis of diseased livers caused by infection with Echinococcus granulosus (E.g). There is evidence that E.g is susceptible to immune escape and tolerance when host expression of immunoinflammation and fibrosis is suppressed, accelerating the progression of CE. Ghrelin has the effect of suppressing immunoinflammation and fibrosis, and whether it is involved in regulating the progression of E.g-infected liver lesions is not clear. METHODS Serum and hepatic Ghrelin levels were observed in E.g-infected mice (4, 12 and 36 weeks) and compared with healthy control groups. Co-localization analysis is performed between protein expression of Ghrelin in and around the hepatic lesions of E.g-infected 12-week mice and protein expression of different hepatic histiocytes by mIHC. HepG2 cells and protoscoleces (PSCs) protein were co-cultured in vitro, as well as PSCs were alone in vitro, followed by exogenously administered of Ghrelin and its receptor blocker, [D-Lys3]-GHRP-6, to assess their regulatory effects on immunoinflammation, fibrosis and survival rate of PSCs. RESULTS Serum Ghrelin levels were increased in E.g-infected 4- and 12-week mice, and reduced in 36-week mice. E.g-infected mice consistently recruited Ghrelin in and around the hepatic lesions, which was extremely strongly co-localized with the protein expression of hepatic stellate cells (HSCs), T cells and the TGF-β1/Smad3 pathway. The secretion of Ghrelin was increased with increasing concentrations of PSCs protein in HepG2 cells culture medium. Moreover, Ghrelin could significantly inhibit the secretion of IL-2, INF-γ and TNF-α, as well as the expression of Myd88/NF-κB and TGF-β1/Smad3 pathway protein, and promoted the secretion of IL-4 and IL-10. Blocking Ghrelin receptor could significantly inhibit PSCs growth in in vitro experiment. CONCLUSION Ghrelin is highly expressed in the early stages of hepatic E.g infection and may be involved in regulating the progression of liver lesions by suppression immunoinflammation and fibrosis.
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Affiliation(s)
- Jiang Zhu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Hongqiong Zhao
- College of Veterinary Medicine, Xinjiang Agricultural University, Xinjiang, China
| | - Aili Aierken
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Tanfang Zhou
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Meng Menggen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Huijing Gao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Rongdong He
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Kalibixiati Aimulajiang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Hao Wen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
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Autier B, Verger A, Plaisse C, Manuel C, Chollet-Krugler M, Preza M, Lundstroem-Stadelmann B, Amela-Cortes M, Aninat C, Samson M, Brandhonneur N, Dion S. PLGA-PEG-COOH nanoparticles are efficient systems for delivery of mefloquine to Echinococcus multilocularis metacestodes. Exp Parasitol 2024; 265:108811. [PMID: 39111383 DOI: 10.1016/j.exppara.2024.108811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 06/10/2024] [Accepted: 08/05/2024] [Indexed: 08/11/2024]
Abstract
Alveolar echinococcosis (AE) is a severe disease caused by the infection with the larval stage of Echinococcus multilocularis, the metacestode. As there is no actual curative drug therapy, recommendations to manage AE patients are based on radical surgery and prophylactic administration of albendazole or mebendazole during 2 years to prevent relapses. There is an urgent need for new therapeutic strategies for the management of AE, as the drugs in use are only parasitostatic, and can induce toxicity. This study aimed at developing a drug delivery system for mefloquine, an antiparasitic compound which is highly active against E. multilocularis in vitro and in experimentally infected mice. We formulated mefloquine-loaded PLGA-PEG-COOH (poly-(lactic-co-glycolic acid)) nanoparticles that exhibit stable physical properties and mefloquine content. These nanoparticles crossed the outer acellular laminated layer of metacestodes in vitro and delivered their content to the inner germinal layer within less than 5 min. The in vitro anti-echinococcal activity of mefloquine was not altered during the formulation process. However, toxicity against hepatocytes was not reduced when compared to free mefloquine. Altogether, this study shows that mefloquine-loaded PLGA-PEG-COOH nanoparticles are promising candidates for drug delivery during AE treatment. However, strategies for direct parasite-specific targeting of these particles should be developed.
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Affiliation(s)
- Brice Autier
- IRSET (UMR_S 1085), INSERM (Institut de Recherche en Santé, Environnement et Travail), EHESP, CHU Rennes, University of Rennes, Rennes, France
| | - Alexis Verger
- CNRS, ISCR (Institut des Sciences Chimiques de Rennes)-UMR 6226, Univ Rennes, F-35000, Rennes, France
| | - Charleen Plaisse
- IRSET (UMR_S 1085), INSERM (Institut de Recherche en Santé, Environnement et Travail), EHESP, University of Rennes, Rennes, France
| | - Christelle Manuel
- IRSET (UMR_S 1085), INSERM (Institut de Recherche en Santé, Environnement et Travail), EHESP, University of Rennes, Rennes, France
| | - Marylène Chollet-Krugler
- CNRS, ISCR (Institut des Sciences Chimiques de Rennes)-UMR 6226, Univ Rennes, F-35000, Rennes, France
| | - Matias Preza
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Britta Lundstroem-Stadelmann
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland; Multidisciplinary Center of Infectious Diseases, University of Bern, Berne, Switzerland
| | - Marian Amela-Cortes
- CNRS, ISCR (Institut des Sciences Chimiques de Rennes)-UMR 6226, Univ Rennes, F-35000, Rennes, France
| | - Caroline Aninat
- INSERM, Université Rennes, INRAE, Institut NuMeCan, Nutrition, Metabolisms and Cancer, F-35000, Rennes, France
| | - Michel Samson
- IRSET (UMR_S 1085), INSERM (Institut de Recherche en Santé, Environnement et Travail), EHESP, University of Rennes, Rennes, France
| | - Nolwenn Brandhonneur
- CNRS, ISCR (Institut des Sciences Chimiques de Rennes)-UMR 6226, Univ Rennes, F-35000, Rennes, France
| | - Sarah Dion
- IRSET (UMR_S 1085), INSERM (Institut de Recherche en Santé, Environnement et Travail), EHESP, University of Rennes, Rennes, France.
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Ma Y, Li J, Liu Y, Zhao H, Qi X, Sun Y, Chen J, Zhou J, Ma X, Wang L. Identification and exploration of a new M2 macrophage marker MTLN in alveolar echinococcosis. Int Immunopharmacol 2024; 131:111808. [PMID: 38457984 DOI: 10.1016/j.intimp.2024.111808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 03/04/2024] [Indexed: 03/10/2024]
Abstract
The pathogen of alveolar echinococcosis (AE) is Echinococcus multilocularis (E. multilocularis), which has the characteristics of diffuse infiltration and growth and has a high mortality rate. At present, the role of macrophages in AE infection has attracted more and more attention, but the new biomarkers and polarization mechanisms of macrophages are rarely studied. In this study, CIBERSORT and WGCNA algorithms were used to establish a weighted gene co-expression network, and MTLN was identified as a biological marker of M2-type macrophages, which participated in energy metabolism of macrophages and mediated inflammatory response, but the role of MTLN in AE was not studied. In this study, liver tissue samples from AE patients were collected and immunofluorescence co-localization showed the relationship between MTLN and macrophage distribution. E. multilocularis infected mouse model was established to analyze the expression of MTLN, liver fibrosis, and inflammatory reaction after E. multilocularis infection. The cell experiment simulated the liver microenvironment of E. multilocularis infected human body and analyzed the expression of MTLN by QRT-PCR and western blot in vitro. The data showed that liver fibrosis occurred in AE patients, and MTLN was activated near the focus. After E. multilocularis infected mice, the expression of MTLN increased with time. In the cell experiment, after the antigen of E. multilocularis protoscolex stimulated normal liver cells, the expression of MTLN increased 48 h, at this time, M2 was up-regulated and M1 was down-regulated. Therefore, MTLN may be the key gene to regulate the polarization of M2 macrophages and cause fibrosis.
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Affiliation(s)
- Yuyu Ma
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang 830011, China
| | - Jiajun Li
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang 830011, China
| | - Yumei Liu
- Xinjiang Medical University Affiliated Traditional Chinese Medicine Hospital, Xinjiang, China
| | - Hui Zhao
- The First Affiliated Hospital of Xinjiang Medical University, Medical Testing Center, Xinjiang, China
| | - Xinwei Qi
- The First Affiliated Hospital of Xinjiang Medical University, Medical Testing Center, Xinjiang, China
| | - Yuqin Sun
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang 830011, China
| | - Jiahui Chen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang 830011, China
| | - Jinping Zhou
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang 830011, China
| | - Xiumin Ma
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang 830011, China.
| | - Liang Wang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang 830011, China; The Fifth Affiliated Hospital of Xinjiang Medical University, Medical Testing Center, Xinjiang, China.
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Yang Y, Wuren T, Wu B, Cheng S, Fan H. The expression of CTLA-4 in hepatic alveolar echinococcosis patients and blocking CTLA-4 to reverse T cell exhaustion in Echinococcus multilocularis-infected mice. Front Immunol 2024; 15:1358361. [PMID: 38605966 PMCID: PMC11007148 DOI: 10.3389/fimmu.2024.1358361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 03/11/2024] [Indexed: 04/13/2024] Open
Abstract
Alveolar echinococcosis (AE) is a zoonotic parasitic disease caused by the infection of Echinococcus multilocularis (E. multilocularis) larvae. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) produces inhibitory signals and induces T cell exhaustion, thereby inhibiting the parasiticidal efficacy of the liver immune system. Therefore, the purpose of this study is to explore how T-cell exhaustion contributes to AE and whether blocking CTLA-4 could reverse T cell exhaustion. Here we discovered that the expression of CTLA-4 was increased in the infiltrating margin around the lesion of the liver from AE patients by using western blot and immunohistochemistry assay. Multiple fluorescence immunohistochemistry identified that CTLA-4 and CD4/CD8 molecules were co-localized. For in vitro experiments, it was found that the sustained stimulation of E. multilocularis antigen could induce T cell exhaustion, blocking CTLA-4-reversed T cell exhaustion. For in vivo experiments, the expression of CTLA-4 was increased in the liver of E. multilocularis-infected mice, and the CTLA-4 and CD4/CD8 molecules were co-localized. Flow cytometry analysis demonstrated that the percentages of both CD4+ T cells and CD8+ T cells in the liver and peripheral blood were significantly increased and induced T exhaustion. When the mice were treated with anti-CTLA-4 antibodies, the number and weight of the lesions decreased significantly. Meanwhile, the flow cytometry results suggested that blocking CTLA-4 could effectively reverse T cell exhaustion and reactivate immune function. Our work reveals that blocking CTLA-4 could effectively reverse the T cell exhaustion caused by E. multilocularis and could be used as a novel target for the treatment of AE.
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Affiliation(s)
- Yuxuan Yang
- Research Center for High Altitude Medicine, Qinghai University, Key Laboratory of High Altitude Medicine (Ministry of Education), Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Laboratory for High Altitude Medicine of Qinghai Province, Xining, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Qinghai University, Xining, Qinghai, China
| | - Tana Wuren
- Research Center for High Altitude Medicine, Qinghai University, Key Laboratory of High Altitude Medicine (Ministry of Education), Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Laboratory for High Altitude Medicine of Qinghai Province, Xining, Qinghai, China
| | - Binjie Wu
- Research Center for High Altitude Medicine, Qinghai University, Key Laboratory of High Altitude Medicine (Ministry of Education), Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Laboratory for High Altitude Medicine of Qinghai Province, Xining, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Qinghai University, Xining, Qinghai, China
| | - Shilei Cheng
- Research Center for High Altitude Medicine, Qinghai University, Key Laboratory of High Altitude Medicine (Ministry of Education), Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Laboratory for High Altitude Medicine of Qinghai Province, Xining, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Qinghai University, Xining, Qinghai, China
| | - Haining Fan
- Qinghai Research Key Laboratory for Echinococcosis, Qinghai University, Xining, Qinghai, China
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, Qinghai, China
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Li J, Zhao H, Lv G, Aimulajiang K, Li L, Lin R, Aji T. Phenotype and function of MAIT cells in patients with alveolar echinococcosis. Front Immunol 2024; 15:1343567. [PMID: 38550591 PMCID: PMC10973110 DOI: 10.3389/fimmu.2024.1343567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 02/29/2024] [Indexed: 04/02/2024] Open
Abstract
Mucosal-associated invariant T (MAIT) cells are a subpopulation of unconventional T cells widely involved in chronic liver diseases. However, the potential role and regulating factors of MAIT cells in alveolar echinococcosis (AE), a zoonotic parasitic disease by Echinococcus multilocularis (E. multilocularis) larvae chronically parasitizing liver organs, has not yet been studied. Blood samples (n=29) and liver specimens (n=10) from AE patients were enrolled. The frequency, phenotype, and function of MAIT cells in peripheral blood and liver tissues of AE patients were detected by flow cytometry. The morphology and fibrosis of liver tissue were examined by histopathology and immunohistochemistry. The correlation between peripheral MAIT cell frequency and serologic markers was assessed by collecting clinicopathologic characteristics of AE patients. And the effect of in vitro stimulation with E. multilocularis antigen (Emp) on MAIT cells. In this study, MAIT cells are decreased in peripheral blood and increased in the close-to-lesion liver tissues, especially in areas of fibrosis. Circulating MAIT exhibited activation and exhaustion phenotypes, and intrahepatic MAIT cells showed increased activation phenotypes with increased IFN-γ and IL-17A, and high expression of CXCR5 chemokine receptor. Furthermore, the frequency of circulating MAIT cells was correlated with the size of the lesions and liver function in patients with AE. After excision of the lesion site, circulating MAIT cells returned to normal levels, and the serum cytokines IL-8, IL-12, and IL-18, associated with MAIT cell activation and apoptosis, were altered. Our results demonstrate the status of MAIT cell distribution, functional phenotype, and migration in peripheral blood and tissues of AE patients, highlighting their potential as biomarkers and therapeutic targets.
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Affiliation(s)
- Jintian Li
- School of Public Healthy, Xinjiang Medical University, Urumqi, China
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hanyue Zhao
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
- Department of Hepatobiliary & Hydatid Disease, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Guodong Lv
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Kalibixiati Aimulajiang
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Liang Li
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Renyong Lin
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
- Department of Hepatobiliary & Hydatid Disease, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Tuerganaili Aji
- School of Public Healthy, Xinjiang Medical University, Urumqi, China
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
- Department of Hepatobiliary & Hydatid Disease, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
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Zhu J, Zhou T, Menggen M, Aimulajiang K, Wen H. Ghrelin regulating liver activity and its potential effects on liver fibrosis and Echinococcosis. Front Cell Infect Microbiol 2024; 13:1324134. [PMID: 38259969 PMCID: PMC10800934 DOI: 10.3389/fcimb.2023.1324134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 12/15/2023] [Indexed: 01/24/2024] Open
Abstract
Ghrelin widely exists in the central nervous system and peripheral organs, and has biological activities such as maintaining energy homeostasis, regulating lipid metabolism, cell proliferation, immune response, gastrointestinal physiological activities, cognition, memory, circadian rhythm and reward effects. In many benign liver diseases, it may play a hepatoprotective role against steatosis, chronic inflammation, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress and apoptosis, and improve liver cell autophagy and immune response to improve disease progression. However, the role of Ghrelin in liver Echinococcosis is currently unclear. This review systematically summarizes the molecular mechanisms by which Ghrelin regulates liver growth metabolism, immune-inflammation, fibrogenesis, proliferation and apoptosis, as well as its protective effects in liver fibrosis diseases, and further proposes the role of Ghrelin in liver Echinococcosis infection. During the infectious process, it may promote the parasitism and survival of parasites on the host by improving the immune-inflammatory microenvironment and fibrosis state, thereby accelerating disease progression. However, there is currently a lack of targeted in vitro and in vivo experimental evidence for this viewpoint.
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Affiliation(s)
- Jiang Zhu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Tanfang Zhou
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Meng Menggen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Kalibixiati Aimulajiang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Hao Wen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
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Ye C, Zhang L, Tang L, Duan Y, Liu J, Zhou H. Host genetic backgrounds: the key to determining parasite-host adaptation. Front Cell Infect Microbiol 2023; 13:1228206. [PMID: 37637465 PMCID: PMC10449477 DOI: 10.3389/fcimb.2023.1228206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/20/2023] [Indexed: 08/29/2023] Open
Abstract
Parasitic diseases pose a significant threat to global public health, particularly in developing countries. Host genetic factors play a crucial role in determining susceptibility and resistance to infection. Recent advances in molecular and biological technologies have enabled significant breakthroughs in understanding the impact of host genes on parasite adaptation. In this comprehensive review, we analyze the host genetic factors that influence parasite adaptation, including hormones, nitric oxide, immune cells, cytokine gene polymorphisms, parasite-specific receptors, and metabolites. We also establish an interactive network to better illustrate the complex relationship between host genetic factors and parasite-host adaptation. Additionally, we discuss future directions and collaborative research priorities in the parasite-host adaptation field, including investigating the impact of host genes on the microbiome, developing more sophisticated models, identifying and characterizing parasite-specific receptors, utilizing patient-derived sera as diagnostic and therapeutic tools, and developing novel treatments and management strategies targeting specific host genetic factors. This review highlights the need for a comprehensive and systematic approach to investigating the underlying mechanisms of parasite-host adaptation, which requires interdisciplinary collaborations among biologists, geneticists, immunologists, and clinicians. By deepening our understanding of the complex interactions between host genetics and parasite adaptation, we can develop more effective and targeted interventions to prevent and treat parasitic diseases. Overall, this review provides a valuable resource for researchers and clinicians working in the parasitology field and offers insights into the future directions of this critical research area.
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Affiliation(s)
- Caixia Ye
- Clinical Medical Research Center, The Second Affiliated Hospital, Army Medical University, Chongqing, China
- Department of Pediatrics, Yunyang Women and Children’s Hospital (Yunyang Maternal and Child Health Hospital), Chongqing, China
| | - Lianhua Zhang
- Clinical Medical Research Center, The Second Affiliated Hospital, Army Medical University, Chongqing, China
- Department of Surgery, Yunyang Women and Children’s Hospital (Yunyang Maternal and Child Health Hospital), Chongqing, China
| | - Lili Tang
- The 3rd Affiliated Teaching Hospital of Xinjiang Medical University (Affiliated Tumor Hospital), Urumqi, China
| | - Yongjun Duan
- Department of Pediatrics, Yunyang Women and Children’s Hospital (Yunyang Maternal and Child Health Hospital), Chongqing, China
| | - Ji Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Hongli Zhou
- Clinical Medical Research Center, The Second Affiliated Hospital, Army Medical University, Chongqing, China
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9
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Beacom S, Nand P, Singh P, Harrison A. Isolated pulmonary hydatid cyst. BMJ Case Rep 2023; 16:e254876. [PMID: 37541696 PMCID: PMC10407385 DOI: 10.1136/bcr-2023-254876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/06/2023] Open
Abstract
Echinococcosis is primarily a disease of developing nations with poor medical infrastructure, where cohabitation with domesticated animals is common. These conditions, in conjunction with the inherent chronicity of the disease, lead to low rates of diagnosis and high morbidity. Robust surveillance is not readily available in communities with the highest disease burden.WHO classifications assist in diagnostic and treatment endeavours especially in countries where this disease is not commonly encountered. However, the understanding of the pathophysiology of echinococcosis and optimal treatment are still lacking in certain patient populations.We present the case of a female from Central Asia with an isolated pulmonary hydatid cyst. She was diagnosed several months after she had an uncomplicated pregnancy and gave birth to a healthy baby girl. Due to a delay in surgical intervention, our patient received a prolonged course of treatment which resulted in a significant reduction in the size of the cyst. Given her improvement, we questioned the current guidelines set by the WHO regarding surgical resection of pulmonary hydatid cysts, compared with an extended course with albendazole in patients with an unusual and protracted course of the disease. Furthermore, we discuss the possible role of pregnancy in exacerbating symptoms of underlying pulmonary hydatid disease.
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Affiliation(s)
- Sabrina Beacom
- Internal Medicine, St. Joseph Medical Center, Stockton, California, USA
| | - Priya Nand
- Infectious Diseases, Touro University, Stockton, California, USA
| | - Parampreet Singh
- Internal Medicine, St. Joseph Medical Center, Stockton, California, USA
| | - Anil Harrison
- Internal Medicine, West Florida Hospital, Pensacola, Florida, USA
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10
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Li B, Wang L, Qi X, Liu Y, Li J, Lv J, Zhou X, Cai X, Shan J, Ma X. NOTCH
signaling inhibition after
DAPT
treatment exacerbates alveolar echinococcosis hepatic fibrosis by blocking
M1
and enhancing
M2
polarization. FASEB J 2023; 37:e22901. [PMID: 37002884 DOI: 10.1096/fj.202202033r] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 01/30/2023] [Accepted: 03/20/2023] [Indexed: 04/03/2023]
Abstract
Alveolar echinococcosis (AE) is a lethal helminthic liver disease caused by persistent infection with Echinococcus multilocularis (E. multilocularis). Although more and more attention has been paid to the macrophages in E. multilocularis infection, the mechanism of macrophage polarization, a critical player in liver immunity, is seldom studied. NOTCH signaling is involved in cell survival and macrophage-mediated inflammation, but the role of NOTCH signaling in AE has been equally elusive. In this study, liver tissue samples from AE patients were collected and an E. multilocularis infected mouse model with or without blocking NOTCH signaling was established to analyze the NOTCH signaling, fibrotic and inflammatory response of the liver after E. multilocularis infection. Changes in polarization and origin of hepatic macrophages were analyzed by flow cytometry. In vitro qRT-PCR and Western blot assays were performed to analyze key receptors and ligands in NOTCH signaling. Our data demonstrated that hepatic fibrosis develops after AE, and the overall blockade of NOTCH signaling caused by DAPT treatment exacerbates the levels of hepatic fibrosis and alters the polarization and origin of hepatic macrophages. Blocking NOTCH signaling in macrophages after E. multilocularis infection downregulates M1 and upregulates M2 expression. The downregulation of NTCH3 and DLL-3 in the NOTCH signaling pathway is significant. Therefore, NOTCH3/DLL3 may be the key pathway in NOTCH signaling regulating macrophage polarization affecting fibrosis caused by AE.
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Affiliation(s)
- Bin Li
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center Tumor Hospital Affiliated to Xinjiang Medical University Urumqi Xinjiang 830011 P.R. China
| | - Liang Wang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center Tumor Hospital Affiliated to Xinjiang Medical University Urumqi Xinjiang 830011 P.R. China
- First Affiliated Hospital of Xinjiang Medical University Urumqi Xinjiang 830011 P.R. China
| | - Xinwei Qi
- First Affiliated Hospital of Xinjiang Medical University Urumqi Xinjiang 830011 P.R. China
| | - Yumei Liu
- Children's Hospital of Xinjiang Uygur Autonomous Region Urumqi Xinjiang 830011 P.R. China
| | - Jiajun Li
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center Tumor Hospital Affiliated to Xinjiang Medical University Urumqi Xinjiang 830011 P.R. China
| | - Jie Lv
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center Tumor Hospital Affiliated to Xinjiang Medical University Urumqi Xinjiang 830011 P.R. China
| | - Xuan Zhou
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center Tumor Hospital Affiliated to Xinjiang Medical University Urumqi Xinjiang 830011 P.R. China
| | - Xuanlin Cai
- First Affiliated Hospital of Xinjiang Medical University Urumqi Xinjiang 830011 P.R. China
| | - Jiaoyu Shan
- College of Basic Medicine of Xinjiang Medical University Urumqi Xinjiang 830011 P.R. China
| | - Xiumin Ma
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center Tumor Hospital Affiliated to Xinjiang Medical University Urumqi Xinjiang 830011 P.R. China
- First Affiliated Hospital of Xinjiang Medical University Urumqi Xinjiang 830011 P.R. China
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11
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Eren S, Aydın S, Kantarci M, Kızılgöz V, Levent A, Şenbil DC, Akhan O. Percutaneous management in hepatic alveolar echinococcosis: A sum of single center experiences and a brief overview of the literature. World J Gastrointest Surg 2023; 15:398-407. [PMID: 37032805 PMCID: PMC10080597 DOI: 10.4240/wjgs.v15.i3.398] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/18/2022] [Accepted: 02/14/2023] [Indexed: 03/27/2023] Open
Abstract
BACKGROUND Hepatic alveolar echinococcosis (HAE) is a serious zoonotic infection that affects humans. It may have a tumor-like appearance at times. Percutaneous treatment of HAE patients is extremely relaxing for them. HAE is a significant human zoonotic infection caused by the fox tapeworm Echinococcus Multilocularis larvae. It possesses the characteristics of an invasive tumor-like lesion due to its infiltrative growth pattern and protracted incubation period. The disease is endemic over central Europe, Asia, and North America.
AIM To characterize HAE patients who were treated percutaneously, their outcomes, and the major technical features of percutaneous treatment in HAE.
METHODS Patients who were treated with percutaneous cyst drainage and/or percutaneous biliary drainage were included in the study. Uncorrected abnormal coagulation values and solid or non-infected HAE with minor necrotic change were excluded.
RESULTS Thirty-two patients underwent percutaneous cyst drainage, two patients underwent percutaneous biliary drainage, and four patients underwent percutaneous biliary drainage alone. Interventional radiology is utilized to drain echinococcal necrosis and abscesses within/without the liver, as well as diseased and clogged bile ducts.
CONCLUSION Percutaneous drainage of cyst contents and/or biliary channels using a minimally invasive technique is a very beneficial. Percutaneous cyst drainage with albendazole therapy improves quality of life in patients who are unable to undergo surgery, even when the mass resolves with long-term treatment.
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Affiliation(s)
- Suat Eren
- Department of Radiology, Faculty of Medicine, Atatürk University, Erzurum 25100, Turkey
| | - Sonay Aydın
- Department of Radiology, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan 24100, Turkey
| | - Mecit Kantarci
- Department of Radiology, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan 24100, Turkey
| | - Volkan Kızılgöz
- Department of Radiology, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan 24100, Turkey
| | - Akın Levent
- Department of Radiology, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan 24100, Turkey
| | - Düzgün Can Şenbil
- Department of Radiology, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan 24100, Turkey
| | - Okan Akhan
- Department of Radiology, Hacettepe University, Ankara 06090, Turkey
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12
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Autier B, Manuel C, Lundstroem-Stadelmann B, Girard JP, Gottstein B, Gangneux JP, Samson M, Robert-Gangneux F, Dion S. Endogenous IL-33 Accelerates Metacestode Growth during Late-Stage Alveolar Echinococcosis. Microbiol Spectr 2023; 11:e0423922. [PMID: 36786637 PMCID: PMC10101030 DOI: 10.1128/spectrum.04239-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 01/28/2023] [Indexed: 02/15/2023] Open
Abstract
During the course of the infectious disease alveolar echinococcosis (AE), the larval stage of Echinococcus multilocularis develops in the liver, where an initial Th1/Th17 immune response may allow its elimination in resistant individuals. In patients susceptible to infection and disease, the Th2 response initiates later, inducing tolerance to the parasite. The role of interleukin 33 (IL-33), an alarmin released during necrosis and known to drive a Th2 immune response, has not yet been described during AE. Wild-type (WT) and IL-33-/- C57BL/6J mice were infected by peritoneal inoculation with E. multilocularis metacestodes and euthanized 4 months later, and their immune response were analyzed. Immunofluorescence staining and IL-33 enzyme-linked immunosorbent assay (ELISA) were also performed on liver samples from human patients with AE. Overall, metacestode lesions were smaller in IL-33-/- mice than in WT mice. IL-33 was detected in periparasitic tissues, but not in mouse or human serum. In infected mice, endogenous IL-33 modified peritoneal macrophage polarization and cytokine profiles. Th2 cytokine concentrations were positively correlated with parasite mass in WT mice, but not in IL-33-/- mice. In human AE patients, IL-33 concentrations were higher in parasitic tissues than in distant liver parenchyma. The main sources of IL-33 were CD31+ endothelial cells of the neovasculature, present within lymphoid periparasitic infiltrates together with FOXP3+ Tregs. In the murine model, periparasitic IL-33 correlated with accelerated parasite growth putatively through the polarization of M2-like macrophages and release of immunosuppressive cytokines IL-10 and transforming growth factor β1 (TGF-β1). We concluded that IL-33 is a key alarmin in AE that contributes to the tolerogenic effect of systemic Th2 cytokines. IMPORTANCE Infection with the metacestode stage of Echinococcus multilocularis, known as alveolar echinococcosis, is the most severe cestodosis worldwide. However, less than 1% of exposed individuals, in which the immune system is unable to control the parasite, develop the disease. The factors responsible for this interindividual variability are not fully understood. In this in vivo study comparing wild-type and IL-33-/- infected mice, together with data from human clinical samples, we determined that IL-33, an alarmin released following tissue injury and involved in the pathogenesis of cancer and asthma, accelerates the progression of the disease by modulating the periparasitic microenvironment. This suggests that targeting IL-33 could be of interest for the management of patients with AE, and that IL-33 polymorphisms could be responsible for increased susceptibility to AE.
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Affiliation(s)
- Brice Autier
- IRSET (UMR_S 1085), INSERM (Institut de recherche en santé, environnement et travail), EHESP, CHU Rennes, University of Rennes, Rennes, France
| | - Christelle Manuel
- IRSET (UMR_S 1085), INSERM (Institut de recherche en santé, environnement et travail), EHESP, University of Rennes, Rennes, France
| | - Britta Lundstroem-Stadelmann
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Jean-Philippe Girard
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, Toulouse, France
| | - Bruno Gottstein
- Institute of Infectious Diseases, Faculty of Medicine, University of Bern, Bern, Switzerland
| | - Jean-Pierre Gangneux
- IRSET (UMR_S 1085), INSERM (Institut de recherche en santé, environnement et travail), EHESP, CHU Rennes, University of Rennes, Rennes, France
| | - Michel Samson
- IRSET (UMR_S 1085), INSERM (Institut de recherche en santé, environnement et travail), EHESP, University of Rennes, Rennes, France
| | - Florence Robert-Gangneux
- IRSET (UMR_S 1085), INSERM (Institut de recherche en santé, environnement et travail), EHESP, CHU Rennes, University of Rennes, Rennes, France
| | - Sarah Dion
- IRSET (UMR_S 1085), INSERM (Institut de recherche en santé, environnement et travail), EHESP, University of Rennes, Rennes, France
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13
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Differential Activity of Human Leukocyte Extract on Systemic Immune Response and Cyst Growth in Mice with Echinococcus Multilocularis Infection After Oral, Subcutaneous and Intraperitoneal Routes of Administration. Helminthologia 2022; 59:341-356. [PMID: 36875680 PMCID: PMC9979067 DOI: 10.2478/helm-2022-0038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 12/04/2022] [Indexed: 02/05/2023] Open
Abstract
Alveolar echinococcosis (AE) caused by the larval stage of Echinococcus multilocularis is serious parasitic diseases associated with the host´s immunosuppression. The effects of human non-immune dialyzable leukocyte extract (DLE) on immune cells in blood and spleen and parasitic cysts weight in Balb/c mice after oral (PO), subcutaneous (SC) and intraperitoneal administration (IP) were compared. The reduction in cysts weight (p < 0.01) was recorded after PO route, whereas moderate reduction was found after SC and IP routes. The elevation of lymphoid populations in blood and spleen was found after PO administration (p < 0.01) in parallel with reduced myeloid population. Infection-elicited decline in B220+B cells was partially abolished by PO route, but DLE routes did not influence the CD3+ T cells. The proportions of CD3+CD4+Th lymphocytes were moderately upregulated, whereas CD3+CD8+Tc populations were reduced after all DLE routes (p < 0.01). PO administration increased CD11b+MHCIIhigh blood monocytes, CD11b-SigleF+ cell, but not CD11b+Si-glecF+ eosinophils in the blood, stimulated after SC and IP routes. DLE induced downregulation of NO production by LPS-stimulated adherent splenocytes ex vivo. Con A-triggered T lymphocyte proliferation was associated with the elevated IFN-γ production and transcription factor Tbet mRNA expression. The alleviation of Th2 (IL-4) and Treg (TGF-β) cytokine production by lymphocytes ex vivo paralleled with downregulation of gene transcription for cytokines, GATA and FoxP3. Reduction of myeloid cells with suppressive activity was found. The SC and IP routes affected partially the cysts weights, diminished significantly gene transcription, NO levels and Th2 and Treg cytokines production. Results showed that PO route of DLE administration was the most effective in ameliorating immunosuppression via stimulation of Th1 type, reducing Th2 and Treg type of immunity and CD3+CD8+Tc lymphocytes in the blood and spleens during E. multilocularis infection in mice.
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14
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Xin Q, Lv W, Xu Y, Luo Y, Zhao C, Wang B, Yuan M, Li H, Song X, Jing T. 2-Deoxy-D-glucose and combined 2-Deoxy-D-glucose/albendazole exhibit therapeutic efficacy against Echinococcus granulosus protoscoleces and experimental alveolar echinococcosis. PLoS Negl Trop Dis 2022; 16:e0010618. [PMID: 35849619 PMCID: PMC9333451 DOI: 10.1371/journal.pntd.0010618] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 07/28/2022] [Accepted: 06/28/2022] [Indexed: 11/23/2022] Open
Abstract
2-Deoxy-D-glucose (2-DG) is a glucose analog used as a promising anticancer agent. It exerts its effects by inhibiting the glycolytic energy metabolism to deplete cells of energy. The larval stage of Echinococcus relies on glycolysis for energy production. Therefore, in this study, we investigated the in vitro and in vivo efficacy of 2-DG against the larval stage of Echinococcus granulosus and E. multilocularis. 2-DG exhibited significant time- and dose-dependent effects against in vitro cultured E. granulosus protoscoleces and E. multilocularis metacestodes. A daily oral administration of 500 mg/kg 2-DG in E. multilocularis-infected mice effectively reduced the weight of metacestodes. Notably, the combination treatment, either 2-DG (500 mg/kg/day) + albendazole (ABZ) (200 mg/kg/day) or 2-DG (500 mg/kg/day) + half-dose of ABZ (100 mg/kg/day), exhibited a potent therapeutic effect against E. multilocularis, significantly promoting the reduction of metacestodes weight compared with the administration of 2-DG or ABZ alone. Furthermore, the combination significantly promoted apoptosis of the cells of metacestodes and inhibited glycolysis in metacestodes, compared with the administration of 2-DG or ABZ alone. In conclusion, 2-DG exerts an effective activity against the larval stage of Echinococcus. Thus, it may be a promising anti-Echinococcus drug, and its combination with ABZ may provide a new strategy for the treatment of echinococcosis in humans. Echinococcosis is a serious but neglected helminthic zoonosis caused by the larval stage of Echinococcus granulosus and E. multilocularis. At present, clinical pharmacotherapy of echinococcosis, such as albendazole (ABZ) and mebendazole, has limited effectiveness. Thus, the development of novel therapeutic drugs for human echinococcosis is urgently needed. 2-Deoxy-D-glucose (2-DG) is a glucose analog used as a promising anticancer agent, and it exerts its effects by inhibiting the glycolytic energy metabolism to deplete cells of energy. Echinococcus in the host depends on glycolysis for energy production and glycolysis intermediates for other metabolic processes. Therefore, in this study, we investigated the efficacy of 2-DG against Echinococcus. 2-DG exerted an effective in vitro and in vivo activity against E. granulosus protoscoleces and E. multilocularis metacestodes, and the combination of this drug with ABZ further improved the therapeutic effect. Therefore, 2-DG can be developed as a promising anti-Echinococcus drug, and its combination with ABZ may provide a new strategy for the treatment of human echinococcosis in the future.
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Affiliation(s)
- Qi Xin
- Department of Pathogenic Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- * E-mail: (QX); (TJ)
| | - Wei Lv
- Department of Pathogenic Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Yunxi Xu
- Department of Pathogenic Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Yumei Luo
- Department of Pathogenic Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Caifang Zhao
- Department of Pathogenic Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Bichen Wang
- Department of Pathogenic Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Miaomiao Yuan
- Department of Pathogenic Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Huanping Li
- Department of Pathogenic Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Xiaoxia Song
- Department of Pathogenic Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Tao Jing
- Department of Pathogenic Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- * E-mail: (QX); (TJ)
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15
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Primary Infection by E. multilocularis Induces Distinct Patterns of Cross Talk between Hepatic Natural Killer T Cells and Regulatory T Cells in Mice. Infect Immun 2022; 90:e0017422. [PMID: 35862712 PMCID: PMC9387288 DOI: 10.1128/iai.00174-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
The larval stage of the helminthic cestode Echinococcus multilocularis can inflict tumor-like hepatic lesions that cause the parasitic disease alveolar echinococcosis in humans, with high mortality in untreated patients. Opportunistic properties of the disease have been established based on the increased incidence in immunocompromised patients and mouse models, indicating that an appropriate adaptive immune response is required for the control of the disease. However, cellular interactions and the kinetics of the local hepatic immune responses during the different stages of infection with E. multilocularis remain unknown. In a mouse model of oral infection that mimics the normal infection route in human patients, the networks of the hepatic immune response were assessed using single-cell RNA sequencing (scRNA-seq) of isolated hepatic CD3+ T cells at different infection stages. We observed an early and sustained significant increase in natural killer T (NKT) cells and regulatory T cells (Tregs). Early tumor necrosis factor (TNF)- and integrin-dependent interactions between these two cell types promote the formation of hepatic lesions. At late time points, downregulation of programmed cell death protein 1 (PD-1) and ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1)-dependent signaling suppress the resolution of parasite-induced pathology. The obtained data provide fresh insight into the adaptive immune responses and local regulatory pathways at different infection stages of E. multilocularis in mice.
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16
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Grüner B, Peters L, Hillenbrand A, Voßberg P, Schweiker J, Rollmann EG, Rodriguez LH, Blumhardt J, Burkert S, Kern P, Köhler C, Soboslay PT. Echinococcus multilocularis specific antibody, systemic cytokine, and chemokine levels, as well as antigen-specific cellular responses in patients with progressive, stable, and cured alveolar echinococcosis: A 10-year follow-up. PLoS Negl Trop Dis 2022; 16:e0010099. [PMID: 35108275 PMCID: PMC8809567 DOI: 10.1371/journal.pntd.0010099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 12/16/2021] [Indexed: 11/18/2022] Open
Abstract
Background The infestation with Echinococcus multilocularis larvae may persist in humans for up to decades without evident clinical symptoms. Longitudinal investigations are needed to understand the dynamic immunological processes in alveolar echinococcosis (AE) patients associated with an active and progressive, a stable or a regressive course of disease. Methodology/Principal findings This study evaluated the E. multilocularis specific antibody responses, systemic cytokine, and chemokine serum levels over a 10-year follow-up period, as well as cellular responsiveness in AE patients. Our results demonstrate a rapid decrease in antibodies against E. multilocularis specific antigen Em2+. Especially in cured patients, these antibodies remained negative, making them a significant predictor for cured AE. E. multilocularis specific IgG4, and indirect hemagglutination IHA decreased later in time, after around 5 years. While total IgE did not show significant dynamics over the course of disease, E. multilocularis specific IgE decreased after one to two years, and increasing levels were a significant predictor of progressive disease. There was no significant change in systemic IL-8, IL-9, CCL18 or CCL20 serum levels over time. Univariate analysis across groups indicated lower IL-8 levels in cured patients; however, this result could not be confirmed by multivariate analysis. Levels of CCL17 decreased during treatment, especially in cured patients, and thus might serve as a predictive or risk factor for progressive disease. Levels of IL-10 and CCL13 decreased during disease, especially after five and ten years of intervention. The E. multilocularis antigen (EmAg) inducible cellular productions of MCP1(CCL13), TARC(CCL17) and PARC(CCL18) were lowest in patients with cured AE and infection-free controls, while the EmAg inducible cellular production of IFN-γ increased after cure. Significant positive cytokine and chemokine correlations were observed in AE patients for IL-9, IL-10, CCL13(MCP-4), CCL17(TARC) and CCL20(LARC)(for all p<0.001). E. multilocularis specific IgG4 response correlated positively with TARC (p<0.001). Both markers enhanced over time in progressive disease and decreased after cure. The levels of IL-8, IL-10, MCP4 and LARC enhanced with AE regression. Conclusions/Significance Repeated biomarker surveys are advisable to evaluate progression or regression of disease during longitudinal follow-up and such analyses can support imaging techniques and improve staging of AE patients. Alveolar echinococcosis (AE) is a severe disease caused by Echinococcus multilocularis, the fox tapeworm. Humans exposed to E. multilocularis may develop severe AE with progressive tissue and organ infiltrating growth of the larval stage. The E. multilocularis larvae appear to have developed effective immune evasion mechanisms which facilitate an asymptomatic incubation and an extended host and parasite coexistence for decades. Over a 10-year follow-up, this investigation aimed to gain a better understanding of the immunological process associated with an active and progressive, a stable or a regressive course of AE. In summary, the rapid decrease of antibodies against the E. multilocularis specific antigen Em2+, especially in cured patients, makes them a significant predictor for cured AE. The positive relation of E. multilocularis specific IgG4 responses and chemokine levels of TARC can indicate AE progression when both enhance over time. Enhanced levels of cytokines IL-8, IL-10, and chemokines MCP4 and LARC may predict AE regression. Repeated biomarker surveys are advisable to evaluate progression or regression of AE during longitudinal follow up, and such analyses can support imaging techniques and improve staging of AE patients.
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Affiliation(s)
- Beate Grüner
- University Hospital of Ulm, Department of Internal Medicine III, Division of Infectious Diseases, Ulm, Germany
| | - Lynn Peters
- University Hospital of Ulm, Department of Internal Medicine III, Division of Infectious Diseases, Ulm, Germany
| | - Andreas Hillenbrand
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm, Germany
| | - Patrick Voßberg
- University Clinics Tübingen, Institute for Tropical Medicine, Eberhard-Karls University, Tübingen, Germany
| | - Jonas Schweiker
- University Clinics Tübingen, Institute for Tropical Medicine, Eberhard-Karls University, Tübingen, Germany
| | - Elisabeth G. Rollmann
- University Clinics Tübingen, Institute for Tropical Medicine, Eberhard-Karls University, Tübingen, Germany
| | - Laura H. Rodriguez
- University Clinics Tübingen, Institute for Tropical Medicine, Eberhard-Karls University, Tübingen, Germany
| | - Jasmin Blumhardt
- University Clinics Tübingen, Institute for Tropical Medicine, Eberhard-Karls University, Tübingen, Germany
| | - Sanne Burkert
- University Hospital of Ulm, Department of Internal Medicine III, Division of Infectious Diseases, Ulm, Germany
| | - Peter Kern
- University Hospital of Ulm, Department of Internal Medicine III, Division of Infectious Diseases, Ulm, Germany
| | - Carsten Köhler
- University Clinics Tübingen, Institute for Tropical Medicine, Eberhard-Karls University, Tübingen, Germany
| | - Peter T. Soboslay
- University Clinics Tübingen, Institute for Tropical Medicine, Eberhard-Karls University, Tübingen, Germany
- * E-mail:
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17
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Wang S, Ma Y, Wang W, Dai Y, Sun H, Li J, Wang S, Li F. Status and prospect of novel treatment options toward alveolar and cystic echinococcosis. Acta Trop 2022; 226:106252. [PMID: 34808118 DOI: 10.1016/j.actatropica.2021.106252] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 10/19/2021] [Accepted: 11/17/2021] [Indexed: 02/07/2023]
Abstract
Cystic echinococcosis (CE) and alveolar echinococcosis (AE) are the two most important global parasitic infectious diseases caused by species of Echinococcus granulosus and E. multilocularis, respectively. Although numerous trials have been performed in search of novel therapeutic options to curb the neglected zoonosis, no other nonsurgical options are currently available to replace the licensed anti echinococcal drugs albendazole (ABZ) and mebendazole (MBZ). A safer and more effective treatment plan for echinococcosis is therefore urgently needed to compensate for this therapeutic shortfall. Here, we present a review of the literature for state-of-the-art valuable anti-parasitic compounds and novel strategies that have proved effective against CE and AE, which includes details about the pharmaceutical type, practical approach, experimental plan, model application and protoscolecidal effects in vivo and in vitro. The content includes the current application of traditional clinical chemicals, the preparation of new compounds with various drug loadings, repurposing findings, combined programs, the prospects for Chinese herbal medicines, non-drug administrations and the exploration of target inhibitors based on open-source information for parasitic genes. Next the conventional experimental projects and pharmacodynamic evaluation methods are systematically summarized and evaluated. The demands to optimize the construction of the echinococcosis model and improve the dynamic monitoring method in vivo are also discussed given the shortcomings of in vivo models and monitoring methods.
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Affiliation(s)
- Sibo Wang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yibo Ma
- Laboratory of Translational Medicine, School of Medicine, Shihezi University, Shihezi 832000, Xinjiang, China
| | - Weishan Wang
- Laboratory of Translational Medicine, School of Medicine, Shihezi University, Shihezi 832000, Xinjiang, China
| | - Yi Dai
- Laboratory of Translational Medicine, School of Medicine, Shihezi University, Shihezi 832000, Xinjiang, China
| | - Haohao Sun
- Laboratory of Translational Medicine, School of Medicine, Shihezi University, Shihezi 832000, Xinjiang, China
| | - Jing Li
- Laboratory of Translational Medicine, School of Medicine, Shihezi University, Shihezi 832000, Xinjiang, China
| | - Shan Wang
- Laboratory of Translational Medicine, School of Medicine, Shihezi University, Shihezi 832000, Xinjiang, China.
| | - Feng Li
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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Liu C, Bi X, Fan H, Ma L, Ge RL. Microcyst fluid promotes the migration and invasion of fibroblasts in the adventitial layer of alveolar echinococcosis. Acta Trop 2021; 223:106084. [PMID: 34389327 DOI: 10.1016/j.actatropica.2021.106084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 07/31/2021] [Accepted: 08/01/2021] [Indexed: 11/24/2022]
Abstract
Alveolar echinococcosis (AE) caused by Echinococcus multilocularis (E. multilocularis), characterized by lesions composed of an aggregate of microcysts embedded in a granulomatous host's reaction. The periphery of parasite granulomas often additionally displays fibrotic reactions of varying intensity, in which E. multilocularis microenvironment fibroblasts (EMFs) laid down collagen. However, the regulation of EMFs by the infiltration of E. multilocularis microcyst fluid (MF) into granulomas remains poorly defined. This study aimed to investigate the effect of MF on migration and invasion of primary isolated EMFs cells. A mouse model of secondary infection with AE was established, and the model construction was evaluated by HE staining. EMFs were cultured in primary by tissue block adherency method. The isolated cells were identified by qPCR, immunofluorescence and Western blot. Then CCK-8 assay, cell migration/invasion assay and flow cytometry were performed to detect the effects of MF on the proliferation, migration, invasion and cell cycle of EMFs, respectively. The expressions of MMP2 and MMP9 at mRNA and protein levels in EMFs were detected by RT-qPCR and Western blot. The effect of PI3K-Akt signal transduction pathway on regulating the expression of MMPs expression was assessed by Western blot. As indicated from the results, EMFs were successfully isolated from the E. multilocularis microenvironment and identified as myofibroblasts. MF significantly facilitated the proliferation and cell cycle progression of EMFs. In addition, MF significantly improved the migration and invasion of EMFs. MF was further confirmed to up-regulate mRNA and protein expressions of MMP2 and MMP9 in EMFs, which was related to the activation of the PI3K-Akt signaling pathway. The present study demonstrates that MF can promote the migration and invasion of EMFs cells significantly, which might be via activating PI3K-Akt signaling pathway.
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Abstract
Hepatic alveolar echinococcosis (HAE) is a rare but severe zoonosis caused by the pseudotumoral intrahepatic development of the larval stage of the tapeworm Echinococcus multilocularis. HAE is present only in the Northern Hemisphere, predominantly in China. Currently, there is a significant resurgence of cases in historically endemic areas associated with emergence of HAE in countries not previously concerned. Today, in European countries, HAE is often discovered by chance; however, clinicians should be made aware of opportunistic infections that progressively emerged recently as a result of therapeutic or pathological immunosuppression. Ultrasonography is the key first-line diagnostic procedure, with specific serology providing confirmation in 95% of the cases. Albendazole, only parasitostatic, is the mainstay for treatment. Surgical resection, if feasible, is the gold standard for treatment, and more patients are currently eligible for this option because of an earlier diagnosis. The prognosis has considerably improved but remains poor in countries where access to care is less favorable.
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Affiliation(s)
- Solange Bresson-Hadni
- Gastroenterology and Hepatology, Faculty of Medicine, University Hospitals of Geneva, Switzerland.,Division of Tropical and Humanitarian Medicine, Faculty of Medicine, University Hospitals of Geneva, Faculty of Medicine, Switzerland.,Laboratory of Parasitology-Mycology, National Reference Center for Echinococcosis, University Hospital of Besançon, Besançon, France
| | - Laurent Spahr
- Gastroenterology and Hepatology, Faculty of Medicine, University Hospitals of Geneva, Switzerland
| | - François Chappuis
- Division of Tropical and Humanitarian Medicine, Faculty of Medicine, University Hospitals of Geneva, Faculty of Medicine, Switzerland
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20
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Jebbawi F, Bellanger AP, Lunström-Stadelmann B, Rufener R, Dosch M, Goepfert C, Gottstein B, Millon L, Grandgirard D, Leib SL, Beldi G, Wang J. Innate and adaptive immune responses following PD-L1 blockade in treating chronic murine alveolar echinococcosis. Parasite Immunol 2021; 43:e12834. [PMID: 33754355 DOI: 10.1111/pim.12834] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 02/10/2021] [Accepted: 03/17/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) immune checkpoint blockade are efficacious in certain cancer therapies. OBJECTIVES The present study aimed to provide a picture about the development of innate and adaptive immune responses upon PD-L1 blockade in treating chronic murine AE. METHODS Immune treatment started at 6 weeks post-E. multilocularis infection, and was maintained for 8 weeks with twice per week anti-PD-L1 administration (intraperitoneal). The study included an outgroup-control with mice perorally medicated with albendazole 5 d/wk, and another one with both treatments combined. Assessment of treatment efficacy was based on determining parasite weight, innate and adaptive immune cell profiles, histopathology and liver tissue cytokine levels. RESULTS/CONCLUSIONS Findings showed that the parasite load was significantly reduced in response to PD-L1 blockade, and this blockade (a) contributed to T-cell activity by increasing CD4+ /CD8+ effector T cells, and decreasing Tregs; (b) had the capacity to restore DCs and Kupffer cells/Macrophages; (c) suppressed NKT and NK cells; and thus (d) lead to an improved control of E. multilocularis infection in mice. This study suggests that the PD-L1 pathway plays an important role by regulating adaptive and innate immune cells against E. multilocularis infection, with significant modulation of tissue inflammation.
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Affiliation(s)
- Fadi Jebbawi
- Department of Visceral Surgery and Medicine, Inselspital, University Hospital of Bern, Bern, Switzerland
| | - Anne-Pauline Bellanger
- Chrono-Environment UMR/CNRS 6249, University of Bourgogne Franche-Comté, Besançon, France.,Parasitology Mycology Department, University Hospital Jean Minjoz, Besancon, France
| | - Britta Lunström-Stadelmann
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Parasitology, University of Bern, Bern, Switzerland
| | - Reto Rufener
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Parasitology, University of Bern, Bern, Switzerland
| | - Michel Dosch
- Department of Visceral Surgery and Medicine, Inselspital, University Hospital of Bern, Bern, Switzerland
| | - Christine Goepfert
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Animal Pathology, COMPATH, University of Bern, Switzerland
| | - Bruno Gottstein
- Institute for Infectious Diseases, University of Bern, Bern, Switzerland
| | - Laurence Millon
- Chrono-Environment UMR/CNRS 6249, University of Bourgogne Franche-Comté, Besançon, France.,Parasitology Mycology Department, University Hospital Jean Minjoz, Besancon, France
| | - Denis Grandgirard
- Institute for Infectious Diseases, University of Bern, Bern, Switzerland
| | - Stephen L Leib
- Institute for Infectious Diseases, University of Bern, Bern, Switzerland
| | - Guido Beldi
- Department of Visceral Surgery and Medicine, Inselspital, University Hospital of Bern, Bern, Switzerland
| | - Junhua Wang
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Parasitology, University of Bern, Bern, Switzerland.,Institute for Infectious Diseases, University of Bern, Bern, Switzerland
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Wang J, Marreros N, Rufener R, Hemphill A, Gottstein B, Lundström-Stadelmann B. Short communication: Efficacy of albendazole in Echinococcus multilocularis-infected mice depends on the functional immunity of the host. Exp Parasitol 2020; 219:108013. [PMID: 33010287 DOI: 10.1016/j.exppara.2020.108013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/08/2020] [Accepted: 09/29/2020] [Indexed: 01/10/2023]
Abstract
Alveolar echinococcosis (AE) is a deadly parasitic disease that requires lifelong treatment with albendazole. Development of host immunity is pivotal with regard to the clinical outcome of AE, but its influence on conventional albendazole treatment is unknown. Using T-cell deficient athymic nude mice, we demonstrated that functional immunity is required for albendazole to be efficacious against murine AE. These results call for attention given the increasing number of immunocompromised patients with AE.
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Affiliation(s)
- Junhua Wang
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Berne, Längassstrasse 122, 3012, Berne, Switzerland; Institute for Infectious Diseases, Faculty of Medicine, University of Berne, Friedbühlstrasse 51, 3010, Berne, Switzerland
| | - Nelson Marreros
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Berne, Längassstrasse 122, 3012, Berne, Switzerland
| | - Reto Rufener
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Berne, Längassstrasse 122, 3012, Berne, Switzerland
| | - Andrew Hemphill
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Berne, Längassstrasse 122, 3012, Berne, Switzerland
| | - Bruno Gottstein
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Berne, Längassstrasse 122, 3012, Berne, Switzerland; Institute for Infectious Diseases, Faculty of Medicine, University of Berne, Friedbühlstrasse 51, 3010, Berne, Switzerland
| | - Britta Lundström-Stadelmann
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Berne, Längassstrasse 122, 3012, Berne, Switzerland.
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22
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Gottstein B, Lachenmayer A, Beldi G, Wang J, Merkle B, Vu XL, Kurath U, Müller N. Diagnostic and follow-up performance of serological tests for different forms/courses of alveolar echinococcosis. Food Waterborne Parasitol 2019; 16:e00055. [PMID: 32095626 PMCID: PMC7034017 DOI: 10.1016/j.fawpar.2019.e00055] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 04/15/2019] [Accepted: 04/16/2019] [Indexed: 02/07/2023] Open
Abstract
Diagnosis of alveolar echinococcosis (AE) is predominantly based on imaging procedures combined with immunodiagnostic testing. In the present study, we retrospectively analyzed the performance of four serological tests (EgHF-ELISA, Em2-ELISA, recEm18-ELISA and Em-Immunoblotting) for initial diagnosis and subsequent monitoring of AE patients. Overall, 101 AE patients were included, grouped according to treatment options and immune status as follows: (A) curative surgical treatment (n = 45 patients), (B) non-radical or palliative surgical treatment (n = 11), (C) benzimidazoles only (n = 20), (D) immunocompromised with radical surgical treatment (n = 11), (E) immunocompromised with benzimidazoles only (n = 4), and finally a group of 10 AE patients (F) that were considered to present so-called “abortive” lesions. Initial (i.e. pretreatment) ELISA-based diagnosis for patients in groups A to E revealed overall diagnostic sensitivities of 95% for EgHF, 86% for Em2, and 80% for recEm18, respectively. Comparatively, the diagnostic sensitivity of Em-Immunoblotting was higher with an overall value of 98%. In group F, only Em-Immunoblotting had an excellent diagnostic sensitivity (100%), whereas the ELISAs had poor sensitivities of 30% (EgHF- and Em2-ELISA) or even 0% (recEm18-ELISA). Serological monitoring of AE patients showed a clear association between a curative development of disease (induced either by surgery or benzimidazole medication) and a negativization in the ELISAs. This effect was most pronounced for the recEm18-ELISA, where 56% negativized following diagnosis/treatment, as compared to 36% for the EgHF-ELISA, and 37% for the Em2-ELISA, respectively. After radical surgery, the mean time until negativization in the recEm18-ELISA was 2.4 years (SD 1.6). This was significantly shorter than the mean 3.9 years (SD 2.5) in those AE patients with non-radical, palliative surgery or ABZ treatment who were able to negativize during the study period (p = 0.048). Conclusively, Em-Immunoblotting appears as the most sensitive test to diagnose active as well as inactive (“abortive”) AE-cases. The inclusion of the ELISAs completes the initial diagnostic picture and offers valuable additional information. Conversely, recEm18-ELISA appears as the currently best serological tool to monitor a regressive and putatively curative course of AE in treated patients.
EgHF-ELISA plus Em-Immunoblotting results in most sensitive initial AE serodiagnosis. Em2- and recEm18-ELISA allow differentiation between AE and CE. recEm18-ELISA is currently the best monitoring test for assessing curative course of AE. Presumably inactive (“abortive”) AE cases were all positive by Em-Immunoblotting.
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Key Words
- ABZ, Albendazole
- AE, Alveolar echinococcosis
- CE, Cystic echinococcosis
- Diagnosis
- ELISA
- ELISA, Enzyme-linked immunosorbent assay
- Echinococcus multilocularis
- EgHF, Echinococcus granulosus hydatid fluid
- Em, Echinococcus multilocularis
- EmVF, Echinococcus multilocularis vesicular fluid
- FDG-PET/CT, fluorodeoxyglucose Positron Emission Tomography/Computed Tomography
- Follow-up serology
- Immunoblotting
- MRI, Magnetic Resonance Imaging
- US, Ultrasonography
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Affiliation(s)
- Bruno Gottstein
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
- Institute for Infectious Diseases, Medical Faculty, University of Bern, Bern, Switzerland
- Corresponding author at: Institute for Infectious Diseases, Medical Faculty, University of Bern, Bern, Switzerland.
| | - Anja Lachenmayer
- Department of Visceral Surgery and Medicine, Visceral Surgery, Inselspital University Hospital Bern and University Bern, Bern, Switzerland
| | - Guido Beldi
- Department of Visceral Surgery and Medicine, Visceral Surgery, Inselspital University Hospital Bern and University Bern, Bern, Switzerland
| | - Junhua Wang
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Bernadette Merkle
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Xuan Lan Vu
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Ursula Kurath
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Norbert Müller
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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23
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Salm LA, Lachenmayer A, Perrodin SF, Candinas D, Beldi G. Surgical treatment strategies for hepatic alveolar echinococcosis. Food Waterborne Parasitol 2019; 15:e00050. [PMID: 32095621 PMCID: PMC7034045 DOI: 10.1016/j.fawpar.2019.e00050] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 03/18/2019] [Accepted: 03/21/2019] [Indexed: 02/08/2023] Open
Abstract
Alveolar echinococcosis is a severe and rare helminthic disease with increasing incidence in endemic regions. Herein, available evidence on curative surgical and potential palliative approaches was reviewed. Such strategies have to be applied in the context of available resources in different health-care systems. Complete resection followed by adjuvant therapy remains the only curative treatment available. Curative surgery is performed by open or laparoscopic approach depending on the extent of the disease and the experience of the surgical team. Palliative resections are typically not indicated, because the availability of endoscopic treatments of biliary complications and long-term benzimidazoles represent efficient alternatives to surgery. Liver transplantation as an alternative to palliative surgery has not been shown to be superior to long-term conservative therapy. Immunosuppressive therapy might additionally contribute to fatal disease recurrence after transplantation.
Alveolar echinococcosis is an aggressive zoonotic infection caused by the parasite Echinococcus multilocularis. Surgery remains the only curative treatment strategy for alveolar echinococcosis. In non-resectable patients, benzimidazole treatment is preferred over palliative surgery or liver transplantation. Follow-up is based on annual serological testing using Em18-Antigen and cross-sectional imaging.
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Affiliation(s)
- L A Salm
- Department of Visceral Surgery and Medicine, University Hospital Bern, Bern, Switzerland
| | - A Lachenmayer
- Department of Visceral Surgery and Medicine, University Hospital Bern, Bern, Switzerland
| | - S F Perrodin
- Department of Visceral Surgery and Medicine, University Hospital Bern, Bern, Switzerland
| | - D Candinas
- Department of Visceral Surgery and Medicine, University Hospital Bern, Bern, Switzerland
| | - G Beldi
- Department of Visceral Surgery and Medicine, University Hospital Bern, Bern, Switzerland
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24
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Wen H, Vuitton L, Tuxun T, Li J, Vuitton DA, Zhang W, McManus DP. Echinococcosis: Advances in the 21st Century. Clin Microbiol Rev 2019; 32:e00075-18. [PMID: 30760475 PMCID: PMC6431127 DOI: 10.1128/cmr.00075-18] [Citation(s) in RCA: 587] [Impact Index Per Article: 97.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Echinococcosis is a zoonosis caused by cestodes of the genus Echinococcus (family Taeniidae). This serious and near-cosmopolitan disease continues to be a significant public health issue, with western China being the area of highest endemicity for both the cystic (CE) and alveolar (AE) forms of echinococcosis. Considerable advances have been made in the 21st century on the genetics, genomics, and molecular epidemiology of the causative parasites, on diagnostic tools, and on treatment techniques and control strategies, including the development and deployment of vaccines. In terms of surgery, new procedures have superseded traditional techniques, and total cystectomy in CE, ex vivo resection with autotransplantation in AE, and percutaneous and perendoscopic procedures in both diseases have improved treatment efficacy and the quality of life of patients. In this review, we summarize recent progress on the biology, epidemiology, diagnosis, management, control, and prevention of CE and AE. Currently there is no alternative drug to albendazole to treat echinococcosis, and new compounds are required urgently. Recently acquired genomic and proteomic information can provide a platform for improving diagnosis and for finding new drug and vaccine targets, with direct impact in the future on the control of echinococcosis, which continues to be a global challenge.
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Affiliation(s)
- Hao Wen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia and WHO Collaborating Centre for Prevention and Care Management of Echinococcosis, Urumqi, China
| | - Lucine Vuitton
- WHO Collaborating Centre for Prevention and Treatment of Human Echinococcosis and French National Centre for Echinococcosis, University Bourgogne Franche-Comte and University Hospital, Besançon, France
| | - Tuerhongjiang Tuxun
- Department of Liver and Laparoscopic Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Jun Li
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia and WHO Collaborating Centre for Prevention and Care Management of Echinococcosis, Urumqi, China
- Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Dominique A Vuitton
- WHO Collaborating Centre for Prevention and Treatment of Human Echinococcosis and French National Centre for Echinococcosis, University Bourgogne Franche-Comte and University Hospital, Besançon, France
| | - Wenbao Zhang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia and WHO Collaborating Centre for Prevention and Care Management of Echinococcosis, Urumqi, China
- Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Donald P McManus
- Molecular Parasitology Laboratory, Infectious Diseases Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
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25
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Wetscher M, Hackländer K, Faber V, Taylor N, Auer H, Duscher GG. Hunting Poses Only a Low Risk for Alveolar Echinococcosis. Front Public Health 2019; 7:7. [PMID: 30761283 PMCID: PMC6361863 DOI: 10.3389/fpubh.2019.00007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 01/09/2019] [Indexed: 12/28/2022] Open
Abstract
The Austrian province of Tyrol belongs to the areas where the alveolar echinococcosis (AE) caused by the fox tapeworm Echinococcus multilocularis (E. multilocularis) is highly endemic. In Central Europe and since 2011 in Austria, a growing incidence of human cases of AE has been observed, presumably linked with increasing fox populations infected by the fox tapeworm E. multilocularis. Hunting and the related activities put hunters in a high-risk group, and they are considered particularly vulnerable for the contraction of an AE. In light of this risk and the increased number of AE cases made public in Austria, the objective of the study was to investigate the prevalence of AE in hunters and to provide a possible connection to the incidence increase. In 2015 and 2016, we examined 813 serums of active hunters from all nine districts of Tyrol and serologically tested them for E. multilocularis antibodies. Twenty-one (2.58%) positive results in ELISA were detected via Western blot (WB), and only one (0.12%) serum showed a low positive reaction. No lesion in the liver parenchyma could be detected by abdominal ultrasonography in this patient so far, but the risk of developing alveolar echinococcosis remains for this WB-positive hunter. Risk factor analysis of these 813 hunters revealed that 697 (85.7%) hunted red foxes regularly and 332 (40.8%) of those skinned them as well. Three hundred and eighteen (39.1%) out of the 813 hunters were owners of hunting dogs; 89 (10.9%) and 243 (29.9%) were owners of non-hunting dogs and cats, respectively. Our results indicate that hunters do not have a greater risk of infection with E. multilocularis compared to non-hunters in Austria. The cause of the unexpected increase in AE cases in Austria remains unclear.
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Affiliation(s)
- Monika Wetscher
- Department of Integrative Biology and Biodiversity Research, Institute of Wildlife Biology and Game Management, University of Natural Resources and Life Sciences, Vienna, Austria
| | - Klaus Hackländer
- Department of Integrative Biology and Biodiversity Research, Institute of Wildlife Biology and Game Management, University of Natural Resources and Life Sciences, Vienna, Austria
| | - Viktoria Faber
- Third Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectious Diseases and Rheumathology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria
| | - Ninon Taylor
- Third Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectious Diseases and Rheumathology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria
| | - Herbert Auer
- Department of Medical Parasitology, Center of Pathophysiology, Infectiology and Immunology, Institute of Specific Prophylaxis and Tropical Medicine, Medical University Vienna, Vienna, Austria
| | - Georg G Duscher
- Department of Pathobiology, Institute of Parasitology, University of Veterinary Medicine, Vienna, Austria
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26
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Wang J, Jebbawi F, Bellanger AP, Beldi G, Millon L, Gottstein B. Immunotherapy of alveolar echinococcosis via PD-1/PD-L1 immune checkpoint blockade in mice. Parasite Immunol 2018; 40:e12596. [PMID: 30315719 PMCID: PMC6587932 DOI: 10.1111/pim.12596] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 09/04/2018] [Accepted: 10/08/2018] [Indexed: 01/01/2023]
Abstract
The growth potential of the tumour‐like Echinococcus multilocularis metacestode (causing alveolar echinococcosis, AE) is directly dependent upon the nature/function of the periparasitic adaptive host immune‐mediated processes. PD‐1/PD‐L1 pathway (programmed cell death 1), which inhibits lymphocytic proliferation in tumour development, is over‐expressed at the chronic stage of AE. We tested the impact of a PD‐1/PD‐L1 pathway blockade on the outcome of both chronic AE (intraperitoneal metacestode inoculation, secondary AE and SAE) and acute AE (peroral egg infection, primary AE and PAE). To assess the parasite proliferation potential, we measured parasite mass weight for SAE and liver lesion number for PAE. In both models, the parasite load was significantly decreased in response to anti‐PD‐L1 antibody treatment. In SAE, anti‐PDL1 administration was associated with increased Th1 response parameters and decreased Treg responses, while in PAE anti‐PDL1 administration was associated with fewer lesions in the liver and decreased Treg/Th2 responses. Our findings highly suggested that a PD‐1/PD‐L1 pathway blockade triggered the host immune responses in favour of an immune‐mediated control of E. multilocularis proliferation. Based on this, future studies that combine PD‐1/PD‐L1 blockade with a parasitostatic albendazole medication may yield in a putatively curative therapeutic approach to control alveolar echinococcosis.
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Affiliation(s)
- Junhua Wang
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Parasitology, University of Bern, Bern, Switzerland
| | - Fadi Jebbawi
- Department of Visceral Surgery and Medicine, Inselspital, University Hospital of Bern, Bern, Switzerland
| | - Anne-Pauline Bellanger
- Chrono-Environment UMR/CNRS 6249, University of Bourgogne Franche-Comté, Besançon, France.,Parasitology Mycology Department, University Hospital Jean Minjoz, Besancon, France
| | - Guido Beldi
- Department of Visceral Surgery and Medicine, Inselspital, University Hospital of Bern, Bern, Switzerland
| | - Laurence Millon
- Chrono-Environment UMR/CNRS 6249, University of Bourgogne Franche-Comté, Besançon, France.,Parasitology Mycology Department, University Hospital Jean Minjoz, Besancon, France
| | - Bruno Gottstein
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Parasitology, University of Bern, Bern, Switzerland
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Foxp3 + T Regulatory Cells as a Potential Target for Immunotherapy against Primary Infection with Echinococcus multilocularis Eggs. Infect Immun 2018; 86:IAI.00542-18. [PMID: 30037796 PMCID: PMC6204723 DOI: 10.1128/iai.00542-18] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 07/13/2018] [Indexed: 02/08/2023] Open
Abstract
Alveolar echinococcosis (AE) is a lethal disease caused by infection with the metacestode stage of the helminth Echinococcus multilocularis, which develops into a tumorlike mass in susceptible intermediate hosts. The growth potential of this parasite stage is directly linked to the nature of the surrounding periparasitic immune-mediated processes. In a first step (experiment 1), mice were orally infected with E. multilocularis eggs, to be used for assessing the hepatic expression profiles of 15 selected cytokine and chemokine genes related to acquired immunity from 21 to 120 days postinfection. The early stage of infection in immunocompetent animals was marked by a mixed Th1/Th2 immune response, as characterized by the concomitant presence of gamma interferon (IFN-γ) and interleukin-4 (IL-4) and their related chemokines. At the late stage of AE, the profile extended to a combined tolerogenic mode including Foxp3, IL-10, and transforming growth factor beta (TGF-β) as key components. In a second step (experiment 2), the effect of T regulatory cell (Treg) deficiency on metacestode growth was assessed in E. multilocularis-infected DEREG (depletion of regulatory T cells) mice upon induction of Treg deficiency with diphtheria toxin (DT). The parasite lesions were significantly smaller in the livers of treated mice than in corresponding control groups. Foxp3+ Tregs appear to be one of the key players in immune-regulatory processes favoring metacestode survival by affecting antigen presentation and suppressing Th1-type immune responses. For these reasons, we suggest that affecting Foxp3+ Tregs could offer an attractive target in the development of an immunotherapy against AE.
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Moazeni M, Asadpour M, Malekpour SH. Influence of hydatid disease on the pregnancy outcomes: An experimental study. J Obstet Gynaecol Res 2018; 44:1896-1901. [PMID: 29974625 DOI: 10.1111/jog.13721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Accepted: 06/01/2018] [Indexed: 11/26/2022]
Abstract
AIM Hydatid disease during pregnancy may lead to various complications in both mother and child. Accordingly, enough knowledge is required to manage these complications. This study was done to evaluate the interaction between hydatid disease and pregnancy in laboratory mice. METHODS Twenty female BALB/c mice (Mus musculus) were divided into test and control groups, 10 animal in each. The mice of the test group were infected intraperitoneally by injection of 1000 protoescolices. Six months after infection, the mice of test and control groups were mated with male mice for a week. After parturition, the size and weight of babies were measured and compared between two groups. RESULTS While all the mice of control group delivered healthy babies, 3 out of 10 mice of test group showed no pregnancy. The infected mice delivered lower number of babies than the mice of control group. The mean size of fetuses or babies obtained from the infected mice were statistically lower than those obtained from the mice of control group (P = 0.000). The weight of babies delivered by the infected mice not only at the time of birth (P = 0.005) but also 10 days after birth (P = 0.021), were significantly lower than those delivered by the mice of control group. The level of progesterone and estradiol in the mice of test group were significantly lower (P = 0.009) and higher (P = 0.043), respectively, in comparison to the mice of control group. CONCLUSION Hydatid disease during pregnancy may considerably affect the pregnancy outcomes.
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Affiliation(s)
- Mohammad Moazeni
- Department of Pathology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Mohammad Asadpour
- Department of Pathology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
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Wang J, Goepfert C, Mueller N, Piersigilli A, Lin R, Wen H, Vuitton DA, Vuitton L, Mueller C, Gottstein B. Larval Echinococcus multilocularis infection reduces dextran sulphate sodium-induced colitis in mice by attenuating T helper type 1/type 17-mediated immune reactions. Immunology 2017; 154:76-88. [PMID: 29121394 PMCID: PMC5904711 DOI: 10.1111/imm.12860] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 10/27/2017] [Accepted: 10/29/2017] [Indexed: 12/13/2022] Open
Abstract
The tumour‐like growth of larval Echinococcus multilocularis tissue (causing alveolar echinococcosis, AE) is directly linked to the nature/orientation of the periparasitic host immune‐mediated processes. Parasite‐mediated immune suppression is a hallmark triggering infection outcome in both chronic human and murine AE. So far, little is known about secondary systemic immune effects of this pathogen on other concomitant diseases, e.g. endogenous gut inflammation. We examined the influence of E. multilocularis infection on murine dextran sodium sulphate (DSS) ‐induced colitis. At 3 months after E. multilocularis infection (chronic stage), the mice were challenged with 3% DSS in the drinking water for 5 days plus subsequently with tap water (alone) for another 4 days. After necropsy, fixed tissues/organs were sectioned and stained with haematoxylin & eosin for assessing inflammatory reactions. Cytokine levels were measured by flow cytometry and quantitative RT‐PCR. Colitis severity was assessed (by board‐certified veterinary pathologists) regarding (i) colon length, (ii) weight loss and (iii) a semi‐quantitative score of morphological changes. The histopathological analysis of the colon showed a significant reduction of DSS‐induced gut inflammation by concomitant E. multilocularis infection, which correlated with down‐regulation of T helper type 1 (Th1)/Th17 T‐cell responses in the colon tissue. Echinococcus multilocularis infection markedly reduced the severity of DSS‐induced gut inflammation upon down‐regulation of Th1/Th17 cytokine expression and attenuation of CD11b+ cell activation. In conclusion, E. multilocularis infection remarkably reduces DSS‐induced colitis in mice by attenuating Th1/Th17‐mediated immune reactions.
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Affiliation(s)
- Junhua Wang
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Parasitology, University of Bern, Bern, Switzerland.,State Key Laboratory Incubation Base of Xinjiang Major Diseases Research (2010DS890294) and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Christine Goepfert
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Animal Pathology, COMPATH, University of Bern, Bern, Switzerland
| | - Norbert Mueller
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Parasitology, University of Bern, Bern, Switzerland
| | - Alessandra Piersigilli
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Animal Pathology, COMPATH, University of Bern, Bern, Switzerland
| | - Renyong Lin
- State Key Laboratory Incubation Base of Xinjiang Major Diseases Research (2010DS890294) and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Hao Wen
- State Key Laboratory Incubation Base of Xinjiang Major Diseases Research (2010DS890294) and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Dominique A Vuitton
- WHO-Collaborating Centre on Prevention and Treatment of Human Echinococcosis and French National Reference Centre on Alveolar Echinococcosis, University of Franche-Comté and University Hospital, Besançon, France
| | - Lucine Vuitton
- WHO-Collaborating Centre on Prevention and Treatment of Human Echinococcosis and French National Reference Centre on Alveolar Echinococcosis, University of Franche-Comté and University Hospital, Besançon, France.,Gastroenterology and Digestive Endoscopy, University Hospital, Besançon, France
| | - Christoph Mueller
- Institute of Pathology, Medical Faculty, University of Bern, Bern, Switzerland
| | - Bruno Gottstein
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Parasitology, University of Bern, Bern, Switzerland
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Bellanger AP, Mougey V, Pallandre JR, Gbaguidi-Haore H, Godet Y, Millon L. Echinococcus multilocularis vesicular fluid inhibits activation and proliferation of natural killer cells. Folia Parasitol (Praha) 2017; 64. [PMID: 28906255 DOI: 10.14411/fp.2017.029] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 08/05/2017] [Indexed: 12/18/2022]
Abstract
Alveolar echinococcosis is a severe chronic helminthic disease that mimics slow-growing liver cancer. The immune evasion strategy of Echinococcus multilocularis Leuckart, 1863 remains poorly understood. The aim of this study was to investigate in vitro the impact of E. multilocularis vesicular fluid (Em-VF) on peripheral blood mononuclear cells (PBMC) and on natural killer (NK) cells. PBMC and NK cells were exposed to Em-VF (1 µg/ml) during six days. The effect of Em-VF was assessed on CD69, viability and proliferation, and on and transforming growth factor β (TGF-β), interferon γ (IFN-γ), interleukin 17 (IL-17) and interleukin 10, using flow cytometry and ELISA, respectively. Exposure to Em-VF had no bearing on PBMC's viability, proliferation and expression of CD69. In contrast, higher levels of IL-17 at day three and of TGF-β at day six were observed in PBMC supernatant after exposure to Em-VF (p < 0.05, Wilcoxon signed-rank test). Exposure to Em-VF induced a significant decrease of CD69 expression of NK cells at day three and a significant decrease of proliferation of NK cells at day six (p < 0.05, Wilcoxon signed-rank test). In contrast, NK cells viability and levels of cytokines did not vary significantly over Em-VF stimulation. Exposure to Em-VF had a significant bearing on activation and proliferation of NK cells. NK cells may play an important role in the immune response of the host against E. multilocularis.
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Affiliation(s)
- Anne-Pauline Bellanger
- Parasitology-Mycology Department, University Hospital, Besancon, France.,Chrono-Environnement CNRS 6249 Research Team, Franche-Comte University, Besancon, France
| | - Valentine Mougey
- Parasitology-Mycology Department, University Hospital, Besancon, France
| | | | | | - Yann Godet
- INSERM Unit 1098, University of Franche-Comte, Besancon, France
| | - Laurence Millon
- Parasitology-Mycology Department, University Hospital, Besancon, France.,Chrono-Environnement CNRS 6249 Research Team, Franche-Comte University, Besancon, France
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Potential risk factors associated with human alveolar echinococcosis: Systematic review and meta-analysis. PLoS Negl Trop Dis 2017; 11:e0005801. [PMID: 28715408 PMCID: PMC5531747 DOI: 10.1371/journal.pntd.0005801] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 07/27/2017] [Accepted: 07/12/2017] [Indexed: 12/28/2022] Open
Abstract
Background Human alveolar echinococcosis (AE) is a severe zoonotic disease caused by the metacestode stage of Echinococcus multilocularis. AE is commonly associated with a long incubation period that may last for more than ten years. The objective of this systematic literature review was to identify and summarize the current knowledge on statistically relevant potential risk factors (PRFs) associated with AE in humans. Methodology/Principal findings Six bibliographic databases were searched, generating a total of 1,009 publications. Following the removal of duplicate records and the exclusion of papers that failed to meet the criteria of a previously agreed a priori protocol, 23 publications were retained; however, 6 of these did not contain data in a format that allowed their inclusion in the meta-analysis. The remaining 17 publications (6 case-control and 11 cross-sectional studies) were meta-analysed to investigate associations between AE and PRFs. Pooled odds ratios (OR) were used as a measure of effect and separately analysed for case-control and cross-sectional studies. In the case-control studies, the following PRFs for human AE showed higher odds of outcome: “dog ownership”, “cat ownership”, “have a kitchen garden”, “occupation: farmer”, “haymaking in meadows not adjacent to water”, “went to forests for vocational reasons”, “chewed grass” and “hunting / handling foxes”. In the cross-sectional studies, the following PRFs showed higher odds of outcome: “dog ownership”, “play with dogs”, “gender: female”, “age over 20 years”, “ethnic group: Tibetan”, “low income”, “source of drinking water other than well or tap”, “occupation: herding” and “low education”. Our meta-analysis confirmed that the chance of AE transmission through ingestion of food and water contaminated with E. multilocularis eggs exists, but showed also that food- and water-borne PRFs do not significantly increase the risk of infection. Conclusions/significance This systematic review analysed international peer-reviewed articles that have over the years contributed to our current understanding of the epidemiology of human AE. The identification of potential risk factors may help researchers and decision makers improve surveillance and/or preventive measures that aim at decreasing human infection with E. multilocularis. More primary studies are needed to confirm potential risk factors and their role in the epidemiology of human AE. Human alveolar echinococcosis is a severe zoonotic disease caused by the metacestode stage of the tapeworm Echinococcus multilocularis. The objective of this systematic literature review was to identify and summarize the current knowledge on potential risk factors associated with human alveolar echinococcosis. The categories of potential risk factors included dog-related factors such as dog ownership or play with dogs; vocational factors like being a farmer or handling foxes; human habits such as chewing grass; gender (being female) and socio-cultural factors like being Tibetan or having a low income or poor education, which may be relevant only in particular endemic areas. The identification of potential risk factors may help identify strategies that aim to decrease human infection with E. multilocularis.
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Wang J, Müller S, Lin R, Siffert M, Vuitton DA, Wen H, Gottstein B. Depletion of FoxP3 + Tregs improves control of larval Echinococcus multilocularis infection by promoting co-stimulation and Th1/17 immunity. IMMUNITY INFLAMMATION AND DISEASE 2017. [PMID: 28621034 PMCID: PMC5691311 DOI: 10.1002/iid3.181] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction The growth potential of the tumor‐like Echinococcus multilocularis metacestode (causing alveolar echinococcosis, AE) is directly linked to the nature/function of the periparasitic host immune‐mediated processes. Previous studies had shown that regulatory T cells (Tregs) become gradually up‐regulated in the course of both chronic human and murine AE. Thus we now tackled the role of FoxP3+ Tregs and FoxP3+‐Treg‐regulated immune response in contributing to the control of this helminthic infection. Methods The infection outcome in E. multilocularis‐infected DEREG mice was measured upon determining parasite load (wet weight of parasitic metacestode tissue). Flow cytometry and qRT‐PCR were used to assess Treg, Th17‐, Th1‐, Th2‐type immune responses and antigen presenting cell activation. Results We showed that E. multilocularis‐infected DEREG‐mice treated with DT (as compared to infected control DEREG‐mice without DT application) exhibited a significantly lower parasite load, associated with a persisting capacity of co‐stimulation, and an increased Th1/Th17‐polarization. Conclusions FoxP3+ Tregs appear as one of the key players in immune regulatory processes favoring (i) metacestode survival by inhibiting the maturation potential of co‐stimulatory activity and (ii) T cell exhaustion (suppressing Th1/Th17‐type immune responses). We showed as well that prospectively, targeting FoxP3+ Tregs could be an option to develop an immunotherapy against AE.
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Affiliation(s)
- Junhua Wang
- Vetsuisse Faculty, Department of Infectious Diseases and Pathobiology, Institute of Parasitology, University of Bern, Bern, Switzerland.,State Key Lab Incubation Base of Xinjiang Major Diseases Research (2010DS890294) and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Stephan Müller
- FACSLab, c/o Institute of Pathology, University of Bern, Bern, Switzerland
| | - Renyong Lin
- State Key Lab Incubation Base of Xinjiang Major Diseases Research (2010DS890294) and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Myriam Siffert
- Vetsuisse Faculty, Department of Infectious Diseases and Pathobiology, Central Animal Facilities, University of Bern, Bern, Switzerland
| | - Dominique A Vuitton
- WHO-Collaborating Centre on Prevention and Treatment of Human Echinococcosis and French National Reference Centre on Alveolar Echinococcosis, University of Franche-Comté and University Hospital, Besançon, France
| | - Hao Wen
- State Key Lab Incubation Base of Xinjiang Major Diseases Research (2010DS890294) and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Bruno Gottstein
- Vetsuisse Faculty, Department of Infectious Diseases and Pathobiology, Institute of Parasitology, University of Bern, Bern, Switzerland
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Ricken FJ, Nell J, Grüner B, Schmidberger J, Kaltenbach T, Kratzer W, Hillenbrand A, Henne-Bruns D, Deplazes P, Moller P, Kern P, Barth TFE. Albendazole increases the inflammatory response and the amount of Em2-positive small particles of Echinococcus multilocularis (spems) in human hepatic alveolar echinococcosis lesions. PLoS Negl Trop Dis 2017; 11:e0005636. [PMID: 28542546 PMCID: PMC5462468 DOI: 10.1371/journal.pntd.0005636] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 06/07/2017] [Accepted: 05/10/2017] [Indexed: 12/17/2022] Open
Abstract
Background Alveolar echinococcosis (AE) is caused by the metacestode stage of Echinococcus multilocularis. The inflammatory response to this infection is influenced by the interaction of the parasite with the host. We aimed to analyze human liver lesions infected with Echinococcus multilocularis and the changes of the cellular infiltrates during albendazole (ABZ) treatment. Methodology/Principal findings We analyzed liver tissue samples from 8 untreated patients, 5 patients treated with two daily doses of 400 mg ABZ for up to two months and 7 patients treated for more than two months with the same ABZ therapy. A broad panel of monoclonal antibodies was used to characterize the lesion by immunohistochemistry. A change in the cellular infiltrate was observed between the different chemotherapy times. During the initial phases of treatment an increase in CD15+ granulocytes and CD68+ histocytes as well as in small particles of Echinococcus multilocularis (spems) was observed in the tissue surrounding the metacestode. Furthermore, we observed an increase in CD4+ T cells, CD20+ B cells and CD38+ plasma cells during a longer duration of treatment. Conclusions/Significance ABZ treatment of AE leads to morphological changes characterized by an initial, predominantly acute, inflammatory response which is gradually replaced by a response of the adaptive immune system. Alveolar echinococcosis (AE) is a life-threatening disease in humans caused by the larval stages of E. multilocularis. It has been shown that the infection in humans is associated with a modulated immune response. Depending on multiple factors, such as the stage of disease, total or partial surgical resection and albendazole (ABZ) therapy are treatments of choice. ABZ is known as a parasitostatic drug that has to be administered for years to suppress metacestode development. Here we compared human liver lesions before and after short and long term treatment with ABZ by immunohistochemistry using a broad panel of antibodies. We found a change in the cellular infiltrate, characterized by a shift to an infiltrate rich in T cells, B cells and plasma cells during long-term treatment with ABZ, including a pronounced detection of small particles of E. multilocularis (spems). We argue that ABZ treatment is likely to change the cellular infiltrate, leading to an enhancement of the host immune response during treatment.
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Affiliation(s)
| | - Juliane Nell
- Institute of Pathology, Ulm University, Ulm, Germany
| | - Beate Grüner
- Division of Infectious Diseases, University Hospital and Medical Center, Ulm, Germany
| | | | - Tanja Kaltenbach
- Department of Medicine I, University Hospital of Ulm, Ulm, Germany
| | - Wolfgang Kratzer
- Department of Medicine I, University Hospital of Ulm, Ulm, Germany
| | - Andreas Hillenbrand
- Department of General and Visceral Surgery, University Hospital of Ulm, Ulm, Germany
| | - Doris Henne-Bruns
- Department of General and Visceral Surgery, University Hospital of Ulm, Ulm, Germany
| | - Peter Deplazes
- Institute of Parasitology, University of Zürich, Zürich, Switzerland
| | - Peter Moller
- Institute of Pathology, Ulm University, Ulm, Germany
| | - Peter Kern
- Division of Infectious Diseases, University Hospital and Medical Center, Ulm, Germany
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Wang J, Gottstein B. Immunoregulation in larval Echinococcus multilocularis infection. Parasite Immunol 2016; 38:182-92. [PMID: 26536823 DOI: 10.1111/pim.12292] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 10/26/2015] [Indexed: 12/24/2022]
Abstract
Alveolar echinococcosis (AE) is a clinically very severe zoonotic helminthic disease, characterized by a chronic progressive hepatic damage caused by the continuous proliferation of the larval stage (metacestode) of Echinococcus multilocularis. The proliferative potential of the parasite metacestode tissue is dependent on the nature/function of the periparasitic immune-mediated processes of the host. Immune tolerance and/or down-regulation of immunity are a marked characteristic increasingly observed when disease develops towards its chronic (late) stage of infection. In this context, explorative studies have clearly shown that T regulatory (Treg) cells play an important role in modulating and orchestrating inflammatory/immune reactions in AE, yielding a largely Th2-biased response, and finally allowing thus long-term parasite survival, proliferation and maturation. AE is fatal if not treated appropriately, but the current benzimidazole chemotherapy is far from optimal, and novel options for control are needed. Future research should focus on the elucidation of the crucial immunological events that lead to anergy in AE, and focus on providing a scientific basis for the development of novel and more effective immunotherapeutical options to support cure AE by abrogating anergy, anticipating also that a combination of immuno- and chemotherapy could provide a synergistic therapeutical effect.
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Affiliation(s)
- J Wang
- Institute of Parasitology, University of Bern, Bern, Switzerland
| | - B Gottstein
- Institute of Parasitology, University of Bern, Bern, Switzerland
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Zhang Q, Ye JR, Ma HM, Wu JJ, Jiang T, Zheng H. Role of immune tolerance in BALB/c mice with anaphylactic shock after Echinococcus granulosus infection. Immunol Res 2016; 64:233-41. [PMID: 26603168 DOI: 10.1007/s12026-015-8741-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
This study tested the hypothesis that immune tolerance mediated by regulatory T (Treg) cells is protective against cystic echinococcosis (CE)-induced anaphylactic shock. BALB/c mice were inoculated with protoscoleces of Echinococcus granulosus. After 3 months, the presence of cysts in the peritoneal cavity was confirmed after which a subset of mice was sensitized using a cyst fluid suspension to induce anaphylactic shock. While IgE levels were significantly higher in both groups inoculated with E. granulosus as compared to the healthy control group (both P < 0.01), sensitized mice had higher IgE levels as compared with those with E. granulosus alone (P < 0.05). Mice inoculated with E. granulosus alone and sensitized mice both had significantly higher histamine levels as compared to the healthy controls. The proportion of CD4(+)CD25(+)Foxp3(+) Treg cells relative to CD4(+) cells was significantly higher in mice inoculated with E. granulosus alone (P < 0.0167); significantly higher interleukin-10 (IL-10) and tumor growth factor-β (TGF-β1) levels were also noted in this group (all P < 0.01). In contrast, IL-13 and IL-17A levels were significantly higher in the sensitized mice (both P < 0.05). Taken together, these data suggest that the biphasic changes in Treg cell and cytokine levels may be associated with anaphylactic shock induced by CE.
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Affiliation(s)
- Qin Zhang
- Department of Anaesthesiology, The First Affiliated Hospital of Xinjiang Medical University, No. 137, Li yu Shan Street, Ürümqi, 830011, China
| | - Jian-Rong Ye
- Department of Anaesthesiology, The First Affiliated Hospital of Xinjiang Medical University, No. 137, Li yu Shan Street, Ürümqi, 830011, China
| | - Hai-Mei Ma
- Department of Anaesthesiology, The First Affiliated Hospital of Xinjiang Medical University, No. 137, Li yu Shan Street, Ürümqi, 830011, China
| | - Jian-Jiang Wu
- Department of Anaesthesiology, The First Affiliated Hospital of Xinjiang Medical University, No. 137, Li yu Shan Street, Ürümqi, 830011, China
| | - Tao Jiang
- Department of Anaesthesiology, The First Affiliated Hospital of Xinjiang Medical University, No. 137, Li yu Shan Street, Ürümqi, 830011, China
| | - Hong Zheng
- Department of Anaesthesiology, The First Affiliated Hospital of Xinjiang Medical University, No. 137, Li yu Shan Street, Ürümqi, 830011, China.
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Abstract
Cystic and alveolar echinococcosis are severe chronic helminthic diseases caused by the cystic growth or the intrahepatic tumour-like growth of the metacestode of Echinococcus granulosus or Echinococcus multilocularis, respectively. Both parasites have evolved sophisticated strategies to escape host immune responses, mainly by manipulating and directing this immune response towards anergy and/or tolerance. Recent research studies have revealed a number of respective immunoregulatory mechanisms related to macrophages and dendritic cell as well as T cell activities (regulatory T cells, Tregs). A better understanding of this complex parasite-host relationship, and the elucidation of specific crucial events that lead to disease, represents targets towards the development of novel treatment strategies and options.
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Vuitton DA, Azizi A, Richou C, Vuitton L, Blagosklonov O, Delabrousse E, Mantion GA, Bresson-Hadni S. Current interventional strategy for the treatment of hepatic alveolar echinococcosis. Expert Rev Anti Infect Ther 2016; 14:1179-1194. [DOI: 10.1080/14787210.2016.1240030] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Lass A, Szostakowska B, Myjak P, Korzeniewski K. Fresh fruits, vegetables and mushrooms as transmission vehicles for Echinococcus multilocularis in highly endemic areas of Poland: reply to concerns. Parasitol Res 2016; 115:3637-42. [PMID: 27249964 PMCID: PMC4980413 DOI: 10.1007/s00436-016-5149-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 05/20/2016] [Indexed: 11/26/2022]
Abstract
Echinococcus multilocularis is a tapeworm that may cause alveolar echinococcosis (AE), one of the most dangerous parasitic zoonoses. As in the case of other foodborne diseases, unwashed fruits and vegetables, contaminated with dispersed forms of E. multilocularis, may serve as an important transmission route for this parasite. In this article, we reply to the incorrect interpretation of results of our study concerning the detection of E. multilocularis DNA in fresh fruit, vegetable and mushroom samples collected from the highly endemic areas of the Warmia-Masuria Province, Poland, to dispel any doubts. The accusations formulated by the commentators concerning our paper are unfounded; moreover, these commentators demand information which was beyond the purview of our study. Making generalisations and drawing far-reaching conclusions from our work is also unjustified. The majority of positive samples were found in only a few hyperendemic communities; this information corresponds with the highest number of both infected foxes and AE cases in humans recorded in this area. Our findings indicate that E. multilocularis is present in the environment and may create a potential risk for the inhabitants. These people should simply be informed to wash fruits and vegetables before eating. No additional far-reaching conclusions should be drawn from our data. We believe these commentators needlessly misinterpreted our results and disseminated misleading information. Nevertheless, we would like to encourage any readers simply to contact us if any aspects of our study are unclear.
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Affiliation(s)
- Anna Lass
- Department of Tropical Parasitology, Institute of Maritime and Tropical Medicine in Gdynia, Medical University of Gdansk, 9b Powstania Styczniowego Str., 81-519, Gdynia, Poland.
| | - Beata Szostakowska
- Department of Tropical Parasitology, Institute of Maritime and Tropical Medicine in Gdynia, Medical University of Gdansk, 9b Powstania Styczniowego Str., 81-519, Gdynia, Poland
| | - Przemysław Myjak
- Department of Tropical Parasitology, Institute of Maritime and Tropical Medicine in Gdynia, Medical University of Gdansk, 9b Powstania Styczniowego Str., 81-519, Gdynia, Poland
| | - Krzysztof Korzeniewski
- Epidemiology and Tropical Medicine Department in Gdynia, Military Institute of Medicine in Warsaw, Grudzińskiego St. 4, 81-103, Gdynia, Poland
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Zhang Q, Ye J, Zheng H. Dexamethasone attenuates echinococcosis-induced allergic reactions via regulatory T cells in mice. BMC Immunol 2016; 17:4. [PMID: 26968945 PMCID: PMC4787038 DOI: 10.1186/s12865-016-0141-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 02/29/2016] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Cystic echinococcosis (CE), caused by infection with Echinococcus granulosus larvae, is a potentially life-threatening disease in humans. Anaphylactic shock caused by CE is very dangerous, and is highly prevalent during surgery. Dexamethasone (DEX) is used clinically before operations to prevent allergic reactions; Regulatory T cells (Treg cells) are believed to be associated with negative immune response, which play an important role in alleviating allergic reactions. However, the association of Treg cells with DEX remains unknown. METHODS In this study, C57BL/6 mice were divided into uninfected group, untreated group and DEX group which were inoculated with protoscoleces from E. granulosus and sensitized using a cyst fluid suspension to induce anaphylactic shock. In addition, the mice in DEX group were treated with 10 mg/kg DEX by intraperitoneal injection 30 min before being sensitized. RESULTS It was found that 93.75 % of all sensitized mice experienced allergic symptoms. The levels of IgE, IgE/IgG, and IgE/IgG1 were significantly higher in both untreated group and DEX group. The proportion of CD4 + CD25 + FOXP3 + Treg cells relative to CD4+ Treg cells, and the levels of interleukin-10 (IL-10) and tumor growth factor-β (TGF-β1) were significantly higher in DEX group. The level of IL-13 was significantly higher in the sensitized mice than in the other groups. These cells may play a key role in alleviating the immune response in CE-induced anaphylactic shock. CONCLUSIONS The protective effect of DEX may be due to Treg cell upregulating IL-10 and TGF-β1 levels, and inhibiting helper T cell 2 cytokines.
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Affiliation(s)
- Qin Zhang
- Department of Anaesthesiology, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China
| | - Jianrong Ye
- Department of Anaesthesiology, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China
| | - Hong Zheng
- Department of Anaesthesiology, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China.
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Expression of Toll-Like Receptors 2 and 4 and Related Cytokines in Patients with Hepatic Cystic and Alveolar Echinococcosis. Mediators Inflamm 2015; 2015:632760. [PMID: 26635448 PMCID: PMC4655286 DOI: 10.1155/2015/632760] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 10/02/2015] [Accepted: 10/08/2015] [Indexed: 12/28/2022] Open
Abstract
Several studies have demonstrated the important role of Toll-like receptors in various parasitic infections. This study aims to explore expression of Toll-like receptors (TLRs) and related cytokines in patients with human cystic echinococcosis (CE) and alveolar echinococcosis (AE). 78 subjects including AE group (N = 28), CE group (N = 22), and healthy controls (HC, N = 28) were enrolled in this study. The mRNA expression levels of TLR2 and TLR4 in blood and hepatic tissue and plasma levels related cytokines were detected by using ELISA. Median levels of TLR2 mRNA in AE and CE groups were significantly elevated as compared with that in healthy control group. Median levels of TLR4 expression were increased in AE and CE. Plasma concentration levels of IL-5, IL-6, and IL-10 were slightly increased in AE and CE groups compared with those in HC group with no statistical differences (p > 0.05). The IL-23 concentration levels were significantly higher in AE and CE groups than that in HC subjects with statistical significance. The increased expression of TLR2 and IL-23 might play a potential role in modulating tissue infiltrative growth of the parasite and its persistence in the human host.
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Vuitton D, Demonmerot F, Knapp J, Richou C, Grenouillet F, Chauchet A, Vuitton L, Bresson-Hadni S, Millon L. Clinical epidemiology of human AE in Europe. Vet Parasitol 2015; 213:110-20. [DOI: 10.1016/j.vetpar.2015.07.036] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Abulaihaiti M, Wu XW, Qiao L, Lv HL, Zhang HW, Aduwayi N, Wang YJ, Wang XC, Peng XY. Efficacy of Albendazole-Chitosan Microsphere-based Treatment for Alveolar Echinococcosis in Mice. PLoS Negl Trop Dis 2015; 9:e0003950. [PMID: 26352932 PMCID: PMC4564103 DOI: 10.1371/journal.pntd.0003950] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Accepted: 07/03/2015] [Indexed: 12/23/2022] Open
Abstract
This study aimed to investigate the pharmacology and anti-parasitic efficacy of albendazole–chitosan microspheres (ABZ-CS-MPs) for established intraperitoneal infections of Echinococcus multilocularis metacestodes in an experimental murine model. Male outbred Kunming mice infected with E. multilocularis Metacestodes were administered with three ABZ formulations, namely, ABZ-CS-MPs, Liposome–Albendazole (L-ABZ), and albendazole tablet (ABZ-T). Each of the ABZ formulations was given orally at three different doses of 37.5, 75, and 150mg/kg, three times a week for 12 weeks postinfection. After administering the drugs, we monitored the pharmacological performance and anti-parasitic efficacy of ABZ-CS-MPs compared with L-ABZ, and ABZ-T treated mice. ABZ-CS-MPs reduced the weight of tissues containing E. multilocularis metacestodes most effectively compared with the ABZ-T group and untreated controls. Metacestode grown was Highly suppressed during treatment with ABZ-CS-MPs. Significantly higher plasma levels of ABZ metabolites were measured in mice treated with ABZ-CS-MPs or L-ABZ compared with ABZ-T. In particular, enhanced ABZ-sulfoxide concentration profiles were observed in the mice given 150mg/kg of ABZ-CS-MPs, but not in the mice treated with L-ABZ. Histological examination showed that damages caused disorganization of both the germinal and laminated layers of liver hyatid cysts, demolishing their characteristic structures after treatment with ABZ-CS-MPs or L-ABZ. Over time, ABZ-CS-MPs treatment induced a shift from Th2-dominant to Th1-dominant immune response. CS-MPs As a new carrier exhibited improved absorption and increased bioavailability of ABZ in the treatment of E. multilocularis infections in mice. Alveolar echinococcosis (AE) is caused by the metacestode stage of Echinococcus multilocularis and is a rare but life-threatening disease. Albendazole is the most frequently used anti-parasitic drugs in patients infected with AE. However, ABZ has only limited water solubility, and small differences in drug solubility may have a major influence on their absorption and resultant pharmacokinetic behavior. Chitosan microspheres as a new carrier increased ABZ absorption and bioavailability. The anti-parasitic efficacy of albendazole–chitosan microspheres (ABZ-CS-MPs) in mice infected with Echinococcus multilocularis was assessed. ABZ-loaded CS-MPs exhibited improved absorption and increased bioavailability in the treatment of E. multilocularis infections in mice compared with those treated with liposome–albendazole and albendazole tablet. ABZ-CS-MPs are in solid form that can be manufactured in capsules or tablets, which can be easily delivered to those in need, particularly those who are nomadic. Therefore, given the merits of low cost, portability, and simple manufacturing, ABZ-CS-MPs are a promising drug to treat alveolar echinococcosis.
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Affiliation(s)
- Maitiseyiti Abulaihaiti
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Xiang-Wei Wu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Lei Qiao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Hai-Long Lv
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Hong-Wei Zhang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Nasrul Aduwayi
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Yan-Jie Wang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Xin-Chun Wang
- Department of Pharmacy, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
- * E-mail: (XCW); (XYP)
| | - Xin-Yu Peng
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
- * E-mail: (XCW); (XYP)
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Gottstein B, Wang J, Boubaker G, Marinova I, Spiliotis M, Müller N, Hemphill A. Susceptibility versus resistance in alveolar echinococcosis (larval infection with Echinococcus multilocularis). Vet Parasitol 2015; 213:103-9. [PMID: 26260407 DOI: 10.1016/j.vetpar.2015.07.029] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Epidemiological studies have demonstrated that the majority of human individuals exposed to infection with Echinococcus spp. eggs exhibit resistance to disease as shown by either seroconversion to parasite--specific antigens, and/or the presence of 'dying out' or 'aborted' metacestodes, not including hereby those individuals who putatively got infected but did not seroconvert and who subsequently allowed no development of the pathogen. For those individuals where infection leads to disease, the developing parasite is partially controlled by host immunity. In infected humans, the type of immune response developed by the host accounts for the subsequent trichotomy concerning the parasite development: (i) seroconversion proving infection, but lack of any hepatic lesion indicating the failure of the parasite to establish and further develop within the liver; or resistance as shown by the presence of fully calcified lesions; (ii) controlled susceptibility as found in the "conventional" alveolar echinococcosis (AE) patients who experience clinical signs and symptoms approximately 5-15 years after infection, and (iii) uncontrolled hyperproliferation of the metacestode due to an impaired immune response (AIDS or other immunodeficiencies). Immunomodulation of host immunity toward anergy seems to be triggered by parasite metabolites. Beside immunomodulating IL-10, TGFβ-driven regulatory T cells have been shown to play a crucial role in the parasite-modulated progressive course of AE. A novel CD4+CD25+ Treg effector molecule FGL2 recently yielded new insight into the tolerance process in Echinococcus multilocularis infection.
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Affiliation(s)
- Bruno Gottstein
- Institute of Parasitology, Vetsuisse Faculty and Faculty of Medicine, University of Bern, Switzerland.
| | - Junhua Wang
- Institute of Parasitology, Vetsuisse Faculty and Faculty of Medicine, University of Bern, Switzerland
| | - Ghalia Boubaker
- Institute of Parasitology, Vetsuisse Faculty and Faculty of Medicine, University of Bern, Switzerland
| | - Irina Marinova
- Institute of Parasitology, Vetsuisse Faculty and Faculty of Medicine, University of Bern, Switzerland
| | - Markus Spiliotis
- Institute of Parasitology, Vetsuisse Faculty and Faculty of Medicine, University of Bern, Switzerland
| | - Norbert Müller
- Institute of Parasitology, Vetsuisse Faculty and Faculty of Medicine, University of Bern, Switzerland
| | - Andrew Hemphill
- Institute of Parasitology, Vetsuisse Faculty and Faculty of Medicine, University of Bern, Switzerland
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Boubaker G, Hemphill A, Huber CO, Spiliotis M, Babba H, Gottstein B. Prevention and Immunotherapy of Secondary Murine Alveolar Echinococcosis Employing Recombinant EmP29 Antigen. PLoS Negl Trop Dis 2015; 9:e0003795. [PMID: 26053794 PMCID: PMC4460070 DOI: 10.1371/journal.pntd.0003795] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 04/28/2015] [Indexed: 12/13/2022] Open
Abstract
Alveolar echinococcosis (AE) is caused by infection with the larval stage of the tapeworm Echinococcus multilocularis. An increasing understanding of immunological events that account for the metacestode survival in human and murine AE infection prompted us to undertake explorative experiments tackling the potential of novel preventive and/or immunotherapeutic measures. In this study, the immunoprotective and immunotherapeutic ability of recombinant EmP29 antigen (rEmP29) was assessed in mice that were intraperitoneally infected with E. multilocularis metacestodes. For vaccination, three intraperitoneal injections with 20μg rEmP29 emulsified in saponin adjuvants were applied over 6 weeks. 2 weeks after the last boost, mice were infected, and at 90 days post-infection, rEmP29-vaccinated mice exhibited a median parasite weight that was reduced by 75% and 59% when compared to NaCl- or saponin–treated control mice, respectively. For immunotherapeutical application, the rEmP29 (20μg) vaccine was administered to experimentally infected mice, starting at 1 month post-infection, three times with 2 weeks intervals. Mice undergoing rEmP29 immunotherapy exhibited a median parasite load that was reduced by 53% and 49% when compared to NaCl- and saponin–treated control mice, respectively. Upon analysis of spleen cells, both, vaccination and treatment with rEmP29, resulted in low ratios of Th2/Th1 (IL-4/IFN-γ) cytokine mRNA and low levels of mRNA coding for IL-10 and IL-2. These results suggest that reduction of the immunosuppressive environment takes place in vaccinated as well as immunotreated mice, and a shift towards a Th1 type of immune response may be responsible for the observed increased restriction of parasite growth. The present study provides the first evidence that active immunotherapy may present a sustainable route for the control of AE. Current medical management of AE that relies on surgery and continuous benzimidazole administration is of limited effectiveness. Therefore, alternative preventive and therapeutic tools need to be explored. Here, we demonstrate that vaccination with recombinant antigen EmP29 (rEmP29), prior or after secondary infection of BALB/c mice, resulted in a significant reduction of the median parasite weight when compared to different control groups. We then characterized the transcription level of splenic IL-4 and IFN-γ cytokines as hallmarks for AE-anti-protective humoral immune reaction (Th2) and for AE-effective (restrictive) cellular response (Th1), respectively. Results revealed that vaccinated mice in pre- or post-infection situation exhibited the lowest IL-4/IFN-γ mRNA ratios. In addition, those groups showed also significantly low levels of IL-10-encoding mRNA coding (immunosuppressive cytokine), as well as IL-2. These findings suggest that reduction of parasite load in rEmP29-vaccinated mice (in pre- or post-infection status) might be triggered by a decline of the immunosuppressive environment and a change of the host immune reaction towards a Th1-re-oriented cell-mediated immune defense. A similar non-specific effect appears also to be yielded by the immunostimulating adjuvants. This study provides the first insight into the potential benefits of antigen-specific immunotherapy as new treatment option of AE.
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Affiliation(s)
- Ghalia Boubaker
- Institute of Parasitology, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
- Faculty of Pharmacy, Department of Clinical Biology B, Laboratory of Medical and Molecular Parasitology–Mycology (LR12ES08), University of Monastir, Monastir, Tunisia
| | - Andrew Hemphill
- Institute of Parasitology, University of Bern, Bern, Switzerland
| | | | - Markus Spiliotis
- Institute of Parasitology, University of Bern, Bern, Switzerland
| | - Hamouda Babba
- Faculty of Pharmacy, Department of Clinical Biology B, Laboratory of Medical and Molecular Parasitology–Mycology (LR12ES08), University of Monastir, Monastir, Tunisia
| | - Bruno Gottstein
- Institute of Parasitology, University of Bern, Bern, Switzerland
- * E-mail:
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Deletion of Fibrinogen-like Protein 2 (FGL-2), a Novel CD4+ CD25+ Treg Effector Molecule, Leads to Improved Control of Echinococcus multilocularis Infection in Mice. PLoS Negl Trop Dis 2015; 9:e0003755. [PMID: 25955764 PMCID: PMC4425495 DOI: 10.1371/journal.pntd.0003755] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 04/13/2015] [Indexed: 02/07/2023] Open
Abstract
Background The growth potential of the tumor-like Echinococcus multilocularis metacestode (causing alveolar echinococcosis, AE) is directly linked to the nature/function of the periparasitic host immune-mediated processes. We previously showed that Fibrinogen-like-protein 2 (FGL2), a novel CD4+CD25+ Treg effector molecule, was over-expressed in the liver of mice experimentally infected with E. multilocularis. However, little is known about its contribution to the control of this chronic helminth infection. Methods/Findings Key parameters for infection outcome in E. multilocularis-infected fgl2-/- (AE-fgl2-/-) and wild type (AE-WT) mice at 1 and 4 month(s) post-infection were (i) parasite load (i. e. wet weight of parasitic metacestode tissue), and (ii) parasite cell proliferation as assessed by determining E. multilocularis 14-3-3 gene expression levels. Serum FGL2 levels were measured by ELISA. Spleen cells cultured with ConA for 48h or with E. multilocularis Vesicle Fluid (VF) for 96h were analyzed ex-vivo and in-vitro. In addition, spleen cells from non-infected WT mice were cultured with rFGL2/anti-FGL2 or rIL-17A/anti-IL-17A for further functional studies. For Treg-immune-suppression-assays, purified CD4+CD25+ Treg suspensions were incubated with CD4+ effector T cells in the presence of ConA and irradiated spleen cells as APCs. Flow cytometry and qRT-PCR were used to assess Treg, Th17-, Th1-, Th2-type immune responses and maturation of dendritic cells. We showed that AE-fgl2-/- mice exhibited (as compared to AE-WT-animals) (a) a significantly lower parasite load with reduced proliferation activity, (b) an increased T cell proliferative response to ConA, (c) reduced Treg numbers and function, and (d) a persistent capacity of Th1 polarization and DC maturation. Conclusions FGL2 appears as one of the key players in immune regulatory processes favoring metacestode survival by promoting Treg cell activity and IL-17A production that contributes to FGL2-regulation. Prospectively, targeting FGL2 could be an option to develop an immunotherapy against AE and other chronic parasitic diseases. In larval E. multilocularis infection causing alveolar echinococcosis (AE) in humans as well as mice, immune tolerance and/or down-regulation of protective immunity is a marked characteristic of this chronic disease. Our study provides a comprehensive evidence for a major involvement of the recently identified CD4+ CD25+ Regulatory T Cell Effector Molecule FGL2 to the outcome of AE. Our major findings are as follows: 1) FGL2 is mostly secreted by Tregs and partly contributes to their functions; 2) FGL2 can down-regulate the maturation of DCs, suppress Th1 and Th17 immune responses, and support Th2 and Treg immune responses, and finally 3) IL-17A contributes to FGL2 secretion. Based on the present findings in mice, we will investigate FGL2 as a potential marker of progression of AE in human patients, or as a potential immunotherapeutical target. Early prediction of parasite regression (currently not yet possible) would allow clinicians to plan for withdrawing benzimidazole treatment, which is currently administered for life. Then, FGL2 should be investigated as a target for an anticipated immunomodulatory treatment of patients with progressive AE, especially of those who are non- or low-responders to benzimidazole treatment, or who suffer from side-effects due to chemotherapy.
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Piarroux M, Gaudart J, Bresson-Hadni S, Bardonnet K, Faucher B, Grenouillet F, Knapp J, Dumortier J, Watelet J, Gerard A, Beytout J, Abergel A, Wallon M, Vuitton DA, Piarroux R. Landscape and climatic characteristics associated with human alveolar echinococcosis in France, 1982 to 2007. Euro Surveill 2015; 20:21118. [PMID: 25990231 DOI: 10.2807/1560-7917.es2015.20.18.21118] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2025] Open
Abstract
Human alveolar echinococcosis (AE) is a severe hepatic disease caused by Echinococcus multilocularis. In France, the definitive and intermediate hosts of E. multilocularis (foxes and rodents, respectively) have a broader geographical distribution than that of human AE. In this two-part study, we describe the link between AE incidence in France between 1982 and 2007 and climatic and landscape characteristics. National-level analysis demonstrated a dramatic increase in AE risk in areas with very cold winters and high annual rainfall levels. Notably, 52% (207/401) of cases resided in French communes (smallest French administrative level) with a mountain climate. The mountain climate communes displayed a 133-fold (95% CI: 95-191) increase in AE risk compared with communes in which the majority of the population resides. A case-control study performed in the most affected areas confirmed the link between AE risk and climatic factors. This arm of the study also revealed that populations residing in forest or pasture areas were at high risk of developing AE. We therefore hypothesised that snow-covered ground may facilitate predators to track their prey, thus increasing E. multilocularis biomass in foxes. Such climatic and landscape conditions could lead to an increased risk of developing AE among humans residing in nearby areas.
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Affiliation(s)
- M Piarroux
- Aix-Marseille University, INSERM-IRD-AMU UMR 912, Marseille, France
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Abstract
Cystic echinococcosis is a chronic infectious disease that results from a host/parasite interaction. Vaccination with ferritin derived from Echinococcus granulosus is a potential preventative treatment. To understand whether ferritin is capable of inducing a host immune response, we investigated the response of dendritic cells (DCs) to both recombinant ferritin protein and the hydatid fluid (HF) of E. granulosus. We evaluated the immunomodulatory potential of these antigens by performing, immunocytochemistry, electron microscopy and in vivo imaging of monocyte-derived murine DCs. During antigen stimulation of DCs, ferritin cause DCs maturation and induced higher levels of surface marker expression and activated T-cell proliferation and migration. On contrary, HF failed to induce surface marker expression and to stimulate T-cell proliferation. In response to HF, DCs produced interleukin-6 (IL-6), but no IL-12 and IL-10. DCs stimulated with ferritin produced high levels of cytokines. Overall, HF appears to induce host immunosuppression in order to ensure parasite survival via inhibits DC maturation and promotes Th2-dependent secretion of cytokines. Although ferritin also promoted DC maturation and cytokine release, it also activates CD4+T-cell proliferation, but regard of the mechanism of the Eg.ferritin induce host to eradicate E. granulosus were not clear.
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Gottstein B, Wang J, Blagosklonov O, Grenouillet F, Millon L, Vuitton DA, Müller N. Echinococcus metacestode: in search of viability markers. ACTA ACUST UNITED AC 2014; 21:63. [PMID: 25429386 PMCID: PMC4245873 DOI: 10.1051/parasite/2014063] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Accepted: 11/11/2014] [Indexed: 12/27/2022]
Abstract
Epidemiological studies have demonstrated that most humans infected with Echinococcus spp. exhibit resistance to disease. When infection leads to disease, the parasite is partially controlled by host immunity: in case of immunocompetence, the normal alveolar echinococcosis (AE) or cystic echinococcosis (CE) situation, the metacestode grows slowly, and first clinical signs appear years after infection; in case of impaired immunity (AIDS; other immunodeficiencies), uncontrolled proliferation of the metacestode leads to rapidly progressing disease. Assessing Echinococcus multilocularis viability in vivo following therapeutic interventions in AE patients may be of tremendous benefit when compared with the invasive procedures used to perform biopsies. Current options are F18-fluorodeoxyglucose-positron emission tomography (FDG-PET), which visualizes periparasitic inflammation due to the metabolic activity of the metacestode, and measurement of antibodies against recEm18, a viability-associated protein, that rapidly regresses upon metacestode inactivation. For Echinococcus granulosus, similar prognosis-associated follow-up parameters are still lacking but a few candidates may be listed. Other possible markers include functional and diffusion-weighted Magnetic Resonance Imaging (MRI), and measurement of products from the parasite (circulating antigens or DNA), and from the host (inflammation markers, cytokines, or chemokines). Even though some of them have been promising in pilot studies, none has been properly validated in an appropriate number of patients until now to be recommended for further use in clinical settings. There is therefore still a need to develop reliable tools for improved viability assessment to provide the sufficient information needed to reliably withdraw anti-parasite benzimidazole chemotherapy, and a basis for the development of new alternative therapeutic tools.
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Affiliation(s)
- Bruno Gottstein
- Institute of Parasitology, Vetsuisse Faculty and Faculty of Medicine, University of Bern, Switzerland
| | - Junhua Wang
- Institute of Parasitology, Vetsuisse Faculty and Faculty of Medicine, University of Bern, Switzerland - WHO-Collaborating Centre for the Prevention and Treatment of Human Echinococcosis, University of Franche-Comté and University Hospital, Besançon, Franche-Comté, France
| | - Oleg Blagosklonov
- Department of Nuclear Medicine, University of Franche-Comté and Jean Minjoz University Hospital, Besançon, Franche-Comté, France - WHO-Collaborating Centre for the Prevention and Treatment of Human Echinococcosis, University of Franche-Comté and University Hospital, Besançon, Franche-Comté, France
| | - Frédéric Grenouillet
- Laboratory of Parasitology-Mycology, Centre Hospitalier Universitaire, Université de Franche Comté, Besançon, France - WHO-Collaborating Centre for the Prevention and Treatment of Human Echinococcosis, University of Franche-Comté and University Hospital, Besançon, Franche-Comté, France
| | - Laurence Millon
- Laboratory of Parasitology-Mycology, Centre Hospitalier Universitaire, Université de Franche Comté, Besançon, France - WHO-Collaborating Centre for the Prevention and Treatment of Human Echinococcosis, University of Franche-Comté and University Hospital, Besançon, Franche-Comté, France
| | - Dominique A Vuitton
- WHO-Collaborating Centre for the Prevention and Treatment of Human Echinococcosis, University of Franche-Comté and University Hospital, Besançon, Franche-Comté, France
| | - Norbert Müller
- Institute of Parasitology, Vetsuisse Faculty and Faculty of Medicine, University of Bern, Switzerland
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Wang J, Lin R, Zhang W, Li L, Gottstein B, Blagosklonov O, Lü G, Zhang C, Lu X, Vuitton DA, Wen H. Transcriptional profiles of cytokine/chemokine factors of immune cell-homing to the parasitic lesions: a comprehensive one-year course study in the liver of E. multilocularis-infected mice. PLoS One 2014; 9:e91638. [PMID: 24637903 PMCID: PMC3956718 DOI: 10.1371/journal.pone.0091638] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Accepted: 02/12/2014] [Indexed: 11/19/2022] Open
Abstract
Pathogenesis of chronically developing alveolar echinococcosis (AE) is characterized by a continuous, granulomatous, periparasitic infiltration of immune cells surrounding the metacestode of Echinococcus multilocularis (E.multilocularis) in the affected liver. A detailed cytokine and chemokine profile analysis of the periparasitic infiltrate in the liver has, however, not yet been carried out in a comprehensive way all along the whole course of infection in E. multilocularis intermediate hosts. We thus assessed the hepatic gene expression profiles of 18 selected cytokine and chemokine genes using qRT-PCR in the periparasitic immune reaction and the subsequent adjacent, not directly affected, liver tissue of mice from day 2 to day 360 post intra-hepatic injection of metacestode. DNA microarray analysis was also used to get a more complete picture of the transcriptional changes occurring in the liver surrounding the parasitic lesions. Profiles of mRNA expression levels in the hepatic parasitic lesions showed that a mixed Th1/Th2 immune response, characterized by the concomitant presence of IL-12α, IFN-γ and IL-4, was established very early in the development of E. multilocularis. Subsequently, the profile extended to a combined tolerogenic profile associating IL-5, IL-10 and TGF-β. IL-17 was permanently expressed in the liver, mostly in the periparasitic infiltrate; this was confirmed by the increased mRNA expression of both IL-17A and IL-17F from a very early stage, with a subsequent decrease of IL-17A after this first initial rise. All measured chemokines were significantly expressed at a given stage of infection; their expression paralleled that of the corresponding Th1, Th2 or Th17 cytokines. In addition to giving a comprehensive insight in the time course of cytokines and chemokines in E. multilocularis lesion, this study contributes to identify new targets for possible immune therapy to minimize E. multilocularis-related pathology and to complement the only parasitostatic effect of benzimidazoles in AE.
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Affiliation(s)
- Junhua Wang
- State Key Lab Incubation Base for Xinjiang Major Diseases Research and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Nuclear Medicine, University of Franche-Comté and Jean Minjoz University Hospital, Besançon, Franche-Comté, France
- Institute of Parasitology, University of Bern, Bern, Switzerland
| | - Renyong Lin
- State Key Lab Incubation Base for Xinjiang Major Diseases Research and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Wenbao Zhang
- State Key Lab Incubation Base for Xinjiang Major Diseases Research and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Liang Li
- State Key Lab Incubation Base for Xinjiang Major Diseases Research and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Bruno Gottstein
- Institute of Parasitology, University of Bern, Bern, Switzerland
| | | | - Guodong Lü
- State Key Lab Incubation Base for Xinjiang Major Diseases Research and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Chuangshan Zhang
- State Key Lab Incubation Base for Xinjiang Major Diseases Research and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xiaomei Lu
- State Key Lab Incubation Base for Xinjiang Major Diseases Research and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Dominique A. Vuitton
- WHO-Collaborating Centre for the Prevention and Treatment of Human Echinococcosis, University of Franche-Comté and University Hospital, Besançon, Franche-Comté, France
- * E-mail: (HW); (DV)
| | - Hao Wen
- State Key Lab Incubation Base for Xinjiang Major Diseases Research and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- * E-mail: (HW); (DV)
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