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Zhang Y, Yue Y, Cheng Y, Jiao H, Yan M. Antigen B from Echinococcus granulosus regulates macrophage phagocytosis by controlling TLR4 endocytosis in immune thrombocytopenia. Chem Biol Interact 2025; 406:111350. [PMID: 39674446 DOI: 10.1016/j.cbi.2024.111350] [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: 10/01/2024] [Revised: 12/07/2024] [Accepted: 12/12/2024] [Indexed: 12/16/2024]
Abstract
Immune thrombocytopenia (ITP) is characterized by a reduction in platelet counts, stemming from an autoimmune-mediated process where platelets are excessively cleared by macrophages. This enhanced phagocytosis is a cardinal pathogenic mechanism in ITP. Antigen B (AgB), a principal component of the Echinococcus granulosus cyst fluid, plays a pivotal role in safeguarding the parasite from host immune defenses by modulating macrophage activation. In this study, we explored the potential of AgB to regulate macrophage activation in the context of ITP. Our observations indicated a diminished presence of M1 macrophages and a reduced phagocytic capacity in patients infected with E. granulosus sensu stricto. We isolated AgB from E. granulosus cyst fluid (EgCF) and discovered that it could suppress the polarization of M1 macrophages and weaken their phagocytic activity via Fcγ receptors, consequently alleviating thrombocytopenia in an ITP mouse model. At the molecular level, AgB was found to suppress the activation of nuclear factor kappa B (NF-κB) and interferon regulatory factor 3 (IRF3) by impeding their nuclear translocation, leading to a reduction in the generation of inflammatory cytokines. Furthermore, AgB was shown to inhibit Toll-like receptor 4 (TLR4) endocytosis and the recycling of CD14. In aggregate, our findings uncover a novel immunomodulatory mechanism of AgB, which suppresses macrophage phagocytosis by regulating TLR4 endocytosis and the subsequent activation of NF-κB and IRF3 signaling pathways. These insights shed new light on the molecular intricacies of E. granulosus-induced immune evasion and suggest that AgB may serve as a promising therapeutic agent for ITP.
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MESH Headings
- Animals
- Toll-Like Receptor 4/metabolism
- Phagocytosis
- Echinococcus granulosus/immunology
- Mice
- Macrophages/immunology
- Macrophages/metabolism
- Endocytosis
- Antigens, Helminth/immunology
- Humans
- Purpura, Thrombocytopenic, Idiopathic/immunology
- Purpura, Thrombocytopenic, Idiopathic/metabolism
- Purpura, Thrombocytopenic, Idiopathic/parasitology
- Purpura, Thrombocytopenic, Idiopathic/pathology
- NF-kappa B/metabolism
- Female
- Mice, Inbred C57BL
- Male
- Interferon Regulatory Factor-3/metabolism
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Affiliation(s)
- Yunfei Zhang
- Department of Pediatrics, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, China
| | - Yingbin Yue
- Department of Pediatrics, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, China
| | - Yongfeng Cheng
- Department of Pediatrics, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, China
| | - Hongjie Jiao
- Department of Pediatrics, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, China
| | - Mei Yan
- Department of Pediatrics, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, China.
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2
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Libertini G. Phenoptosis and the Various Types of Natural Selection. BIOCHEMISTRY. BIOKHIMIIA 2023; 88:2007-2022. [PMID: 38462458 DOI: 10.1134/s0006297923120052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/14/2023] [Accepted: 09/17/2023] [Indexed: 03/12/2024]
Abstract
In the first description of evolution, the fundamental mechanism is the natural selection favoring the individuals best suited for survival and reproduction (selection at the individual level or classical Darwinian selection). However, this is a very reductive description of natural selection that does not consider or explain a long series of known phenomena, including those in which an individual sacrifices or jeopardizes his life on the basis of genetically determined mechanisms (i.e., phenoptosis). In fact, in addition to (i) selection at the individual level, it is essential to consider other types of natural selection such as those concerning: (ii) kin selection and some related forms of group selection; (iii) the interactions between the innumerable species that constitute a holobiont; (iv) the origin of the eukaryotic cell from prokaryotic organisms; (v) the origin of multicellular eukaryotic organisms from unicellular organisms; (vi) eusociality (e.g., in many species of ants, bees, termites); (vii) selection at the level of single genes, or groups of genes; (viii) the interactions between individuals (or more precisely their holobionts) of the innumerable species that make up an ecosystem. These forms of natural selection, which are all effects and not violations of the classical Darwinian selection, also show how concepts as life, species, individual, and phenoptosis are somewhat not entirely defined and somehow arbitrary. Furthermore, the idea of organisms selected on the basis of their survival and reproduction capabilities is intertwined with that of organisms also selected on the basis of their ability to cooperate and interact, even by losing their lives or their distinct identities.
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Affiliation(s)
- Giacinto Libertini
- Italian Society for Evolutionary Biology (ISEB), Asti, 14100, Italy.
- Department of Translational Medical Sciences, Federico II University of Naples, Naples, 80131, Italy
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3
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Vanhooren M, Stoefs A, Van Den Broucke S, Van Esbroeck M, Demuyser T, Kindt S. Intestinal helminthic infections: a narrative review to guide the hepatogastroenterologist. Acta Gastroenterol Belg 2023; 86:460-473. [PMID: 37814562 DOI: 10.51821/86.3.11895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/11/2023]
Abstract
Intestinal helminthic infections are not uncommon in Western Europe, mainly due to modern travel, emigration and globalization. Moreover, some helminthic infections are endemic in Western Europe and are part of the everyday clinical practice. The hepatogastroenterologist should therefore recognize and manage these patients or at least refer them to appropriate reference centers. Signs and symptoms are often unspecific or even absent. Discerning the disease at an early stage avoids expensive diagnostic testing, life-threatening complications and in some cases even further spread of the disease. This review article aims to guide the hepatogastroenterologist when suspecting a helminthic infection by addressing the most prevalent symptoms, summarizing the most probable associated helminthic entities, highlighting practical steps in diagnosis and available treatments.
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Affiliation(s)
- M Vanhooren
- Department of Gastroenterology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - A Stoefs
- Department of Microbiology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - S Van Den Broucke
- Department of Clinical Sciences, Institute of Tropical Medicine Antwerp (ITMA), Antwerp, Belgium
| | - M Van Esbroeck
- Department of Clinical Sciences, Institute of Tropical Medicine Antwerp (ITMA), Antwerp, Belgium
| | - T Demuyser
- Department of Microbiology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
- AIMS lab, Center for Neurosciences, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - S Kindt
- Department of Gastroenterology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
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4
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Atagozli T, Elliott DE, Ince MN. Helminth Lessons in Inflammatory Bowel Diseases (IBD). Biomedicines 2023; 11:1200. [PMID: 37189818 PMCID: PMC10135676 DOI: 10.3390/biomedicines11041200] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/10/2023] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
Helminths are multicellular invertebrates that colonize the gut of many vertebrate animals including humans. This colonization can result in pathology, which requires treatment. It can also lead to a commensal and possibly even a symbiotic relationship where the helminth and the host benefit from each other's presence. Epidemiological data have linked helminth exposure to protection from immune disorders that include a wide range of diseases, such as allergies, autoimmune illnesses, and idiopathic inflammatory disorders of the gut, which are grouped as inflammatory bowel diseases (IBD). Treatment of moderate to severe IBD involves the use of immune modulators and biologics, which can cause life-threatening complications. In this setting, their safety profile makes helminths or helminth products attractive as novel therapeutic approaches to treat IBD or other immune disorders. Helminths stimulate T helper-2 (Th2) and immune regulatory pathways, which are targeted in IBD treatment. Epidemiological explorations, basic science studies, and clinical research on helminths can lead to the development of safe, potent, and novel therapeutic approaches to prevent or treat IBD in addition to other immune disorders.
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Affiliation(s)
- Tyler Atagozli
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Iowa Carver College of Medicine, Iowa City, IA 52246, USA
| | - David E. Elliott
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Iowa Carver College of Medicine, Iowa City, IA 52246, USA
- Iowa City Veterans Affairs Medical Center, Iowa City, IA 52246, USA
| | - Mirac Nedim Ince
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Iowa Carver College of Medicine, Iowa City, IA 52246, USA
- Iowa City Veterans Affairs Medical Center, Iowa City, IA 52246, USA
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Parker W, Patel E, Jirků-Pomajbíková K, Laman JD. COVID-19 morbidity in lower versus higher income populations underscores the need to restore lost biodiversity of eukaryotic symbionts. iScience 2023; 26:106167. [PMID: 36785786 PMCID: PMC9908430 DOI: 10.1016/j.isci.2023.106167] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023] Open
Abstract
The avoidance of infectious disease by widespread use of 'systems hygiene', defined by hygiene-enhancing technology such as sewage systems, water treatment facilities, and secure food storage containers, has led to a dramatic decrease in symbiotic helminths and protists in high-income human populations. Over a half-century of research has revealed that this 'biota alteration' leads to altered immune function and a propensity for chronic inflammatory diseases, including allergic, autoimmune and neuropsychiatric disorders. A recent Ethiopian study (EClinicalMedicine 39: 101054), validating predictions made by several laboratories, found that symbiotic helminths and protists were associated with a reduced risk of severe COVID-19 (adjusted odds ratio = 0.35; p<0.0001). Thus, it is now apparent that 'biome reconstitution', defined as the artificial re-introduction of benign, symbiotic helminths or protists into the ecosystem of the human body, is important not only for alleviation of chronic immune disease, but likely also for pandemic preparedness.
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Affiliation(s)
| | | | - Kateřina Jirků-Pomajbíková
- Institute of Parasitology, Biology Centre, Czech Academy of Sciences, 370 05 České Budějovice, Czech Republic
- Faculty of Science, University of South Bohemia, 370 05 České Budějovice, Czech Republic
| | - Jon D. Laman
- Department of Pathology and Medical Biology, University Groningen, University Medical Center Groningen, Groningen, the Netherlands
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6
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Bao J, Qi W, Sun C, Tian M, Jiao H, Guo G, Guo B, Ren Y, Zheng H, Wang Y, Yan M, Zhang Z, McManus DP, Li J, Zhang W. Echinococcus granulosus sensu stricto and antigen B may decrease inflammatory bowel disease through regulation of M1/2 polarization. Parasit Vectors 2022; 15:391. [PMID: 36289514 PMCID: PMC9608937 DOI: 10.1186/s13071-022-05498-y] [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: 04/14/2022] [Accepted: 09/16/2022] [Indexed: 11/17/2022] Open
Abstract
Background Inflammatory bowel disease (IBD) is a chronic idiopathic disease characterized by inflammation-related epithelial barrier damage in the intestinal tract. Helminth infection reduces autoimmune disease symptoms through regulation of inflammatory responses based on hygiene theory. However, the underlying mechanisms remain unclear. Methods BALB/c mice were infected with microcysts of E. granulosus sensu stricto and drank water containing 3.5% dextran sodium sulfate (DSS) at the 100th day post-infection. After 7 days of drinking DSS, the mouse body weight change and disease activity index (DAI) were recorded every day, and colon length and histological score were evaluated after sacrifice. After injection with antigen B (AgB), inducible nitric oxide synthase (iNOS) and Fizz1 expression and F4/80+CD11c+ M1 and F4/80+CD206+ M2 in the peritoneal cells and colon tissues were analysed by qPCR and flow cytometry, respectively. Gut microbiota were profiled by 16S rRNA sequencing of the mouse faecal samples. For in vitro assay, RAW264.7 macrophages were cultured in medium containing AgB before induction by lipopolysaccharide (LPS). Then, NO in the supernatant was measured, and the expression of cytokine genes associated with macrophages were determined by qRT-PCR. Results Echinococcus granulosus s.s. infection and AgB significantly reduced the symptoms and histological scores of IBD induced by DSS (P < 0.05). Flow cytometry showed that AgB inoculation increased F4/80+ and CD206+ in peritoneal cells. The results of qPCR showed that AgB significantly decreased iNOS and increased Fizz1 expression in the colon of mice inoculated by DSS (P < 0.05). Furthermore, AgB injection led to significant changes in the profiles of five genera (Paraprevotella, Odoribacter, Clostridium cluster XlVa, Oscillibacter, and Flavonifractor) in faecal samples. In vitro analysis showed that AgB reduced NO levels (P < 0.01), with a significant decrease in iNOS expression (P < 0.05) in RAW264.7 cells induced by LPS. Conclusions Echinococcus granulosus infection and AgB may improve IBD conditions by inducing an M2-predominant cellular (F4/80+ CD206+) profile and decreasing type 1 macrophages (F4/80+CD11c+) in the intestinal lamina propria. In addition, AgB intervention induced changes in the microbiota condition of the gastrointestinal duct and reversed NO expression. Thus, AgB may be a drug candidate for IBD treatment. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13071-022-05498-y.
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Affiliation(s)
- Jianling Bao
- grid.13394.3c0000 0004 1799 3993State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, 830054 Xinjiang China
| | - Wenjing Qi
- grid.13394.3c0000 0004 1799 3993State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, 830054 Xinjiang China
| | - Chang Sun
- grid.13394.3c0000 0004 1799 3993State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, 830054 Xinjiang China
| | - Mengxiao Tian
- grid.13394.3c0000 0004 1799 3993State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, 830054 Xinjiang China ,grid.13394.3c0000 0004 1799 3993Basic Medicine College, Xinjiang Medical University, Urumqi, 830011 Xinjiang China
| | - Hongjie Jiao
- grid.13394.3c0000 0004 1799 3993State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, 830054 Xinjiang China
| | - Gang Guo
- grid.13394.3c0000 0004 1799 3993State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, 830054 Xinjiang China
| | - Baoping Guo
- grid.13394.3c0000 0004 1799 3993State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, 830054 Xinjiang China
| | - Yuan Ren
- grid.13394.3c0000 0004 1799 3993State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, 830054 Xinjiang China
| | - Huajun Zheng
- NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai, 200032 China ,grid.464306.30000 0004 0410 5707Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, 201203 China
| | - Yuezhu Wang
- grid.464306.30000 0004 0410 5707Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, 201203 China
| | - Mei Yan
- grid.13394.3c0000 0004 1799 3993State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, 830054 Xinjiang China
| | - Zhaoxia Zhang
- grid.13394.3c0000 0004 1799 3993State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, 830054 Xinjiang China
| | - Donald P. McManus
- grid.1049.c0000 0001 2294 1395Molecular Parasitology Laboratory, Infectious Diseases Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD Australia
| | - Jun Li
- grid.13394.3c0000 0004 1799 3993State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, 830054 Xinjiang China
| | - Wenbao Zhang
- grid.13394.3c0000 0004 1799 3993State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, 830054 Xinjiang China ,grid.13394.3c0000 0004 1799 3993Basic Medicine College, Xinjiang Medical University, Urumqi, 830011 Xinjiang China
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7
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Protective effect and mechanism of Schistosoma japonicum soluble egg antigen against type 1 diabetes in NOD mice. Int J Diabetes Dev Ctries 2022. [DOI: 10.1007/s13410-021-00970-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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8
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Smith AD, Chen C, Cheung L, Ward R, Hintze KJ, Dawson HD. Resistant Potato Starch Alters the Cecal Microbiome and Gene Expression in Mice Fed a Western Diet Based on NHANES Data. Front Nutr 2022; 9:782667. [PMID: 35392294 PMCID: PMC8983116 DOI: 10.3389/fnut.2022.782667] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 01/26/2022] [Indexed: 11/13/2022] Open
Abstract
Several studies indicate that the four major types of resistant starch (RS1-4) are fermented in the cecum and colon to produce short-chain fatty acids (SCFAs) and can alter the microbiome and host physiology. However, nearly all these studies were conducted in rodents fed with a diet that does not approximate what is typically consumed by humans. To address this, mice were fed a Total Western Diet (TWD) based on National Health and Nutrition Examination Survey (NHANES) data that mimics the macro and micronutrient composition of a typical American diet for 6 weeks and then supplemented with 0, 2, 5, or 10% of the RS2, resistant potato starch (RPS), for an additional 3 weeks. The cecal microbiome was analyzed by 16S sequencing. The alpha-diversity of the microbiome decreased with increasing consumption of RPS while a beta-diversity plot showed four discreet groupings based on the RPS level in the diet. The relative abundance of various genera was altered by feeding increasing levels of RPS. In particular, the genus Lachnospiraceae NK4A136 group was markedly increased. Cecal, proximal, and distal colon tissue mRNA abundance was analyzed by RNASeq. The cecal mRNA abundance principal component analysis showed clear segregation of the four dietary groups whose separation decreased in the proximal and distal colon. Differential expression of the genes was highest in the cecum, but substantially decreased in the proximal colon (PC) and distal colon (DC). Most differentially expressed genes were unique to each tissue with little overlap in between. The pattern of the observed gene expression suggests that RPS, likely through metabolic changes secondary to differences in microbial composition, appears to prime the host to respond to a range of pathogens, including viruses, bacteria, and parasites. In summary, consumption of dietary RPS led to significant changes to the microbiome and gene expression in the cecum and to a lesser extent in the proximal and distal colon.
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Affiliation(s)
- Allen D. Smith
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD, United States
- *Correspondence: Allen D. Smith
| | - Celine Chen
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD, United States
| | - Lumei Cheung
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD, United States
| | - Robert Ward
- Department of Nutrition, Dietetics and Food Sciences, Utah State University, Logan, UT, United States
| | - Korry J. Hintze
- Department of Nutrition, Dietetics and Food Sciences, Utah State University, Logan, UT, United States
| | - Harry D. Dawson
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD, United States
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9
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Shi W, Xu N, Wang X, Vallée I, Liu M, Liu X. Helminth Therapy for Immune-Mediated Inflammatory Diseases: Current and Future Perspectives. J Inflamm Res 2022; 15:475-491. [PMID: 35087284 PMCID: PMC8789313 DOI: 10.2147/jir.s348079] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 01/11/2022] [Indexed: 12/17/2022] Open
Affiliation(s)
- Wenjie Shi
- Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, People’s Republic of China
| | - Ning Xu
- Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, People’s Republic of China
| | - Xuelin Wang
- Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, People’s Republic of China
| | - Isabelle Vallée
- UMR BIPAR, Anses, INRAE, Ecole Nationale Vétérinaire d’Alfort, Laboratoire de Santé Animale, Maisons-Alfort, France
| | - Mingyuan Liu
- Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, People’s Republic of China
| | - Xiaolei Liu
- Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, People’s Republic of China
- Correspondence: Xiaolei Liu; Mingyuan Liu, Tel +86-15943092280; +86-13019125996, Email ;
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10
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Abstract
Transforming Growth Factor-β is a potent regulator of the immune system, acting at every stage from thymic differentiation, population of the periphery, control of responsiveness, tissue repair and generation of memory. It is therefore a central player in the immune response to infectious pathogens, but its contribution is often clouded by multiple roles acting on different cells in time and space. Hence, context is all-important in understanding when TGF-β is beneficial or detrimental to the outcome of infection. In this review, a full range of infectious agents from viruses to helminth parasites are explored within this framework, drawing contrasts and general conclusions about the importance of TGF-β in these diseases.
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Affiliation(s)
- Rick M Maizels
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
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11
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Long SR, Liu RD, Kumar DV, Wang ZQ, Su CW. Immune Protection of a Helminth Protein in the DSS-Induced Colitis Model in Mice. Front Immunol 2021; 12:664998. [PMID: 33995396 PMCID: PMC8117093 DOI: 10.3389/fimmu.2021.664998] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 04/08/2021] [Indexed: 12/23/2022] Open
Abstract
Inflammatory bowel disease (IBD) increases the risk of colorectal cancer, and it has the potential to diminish the quality of life. Recent clinical and experimental evidence demonstrate protective aspects of parasitic helminth infection against IBD. Reports have highlighted the potential use of helminths and their byproducts as potential treatment for IBD. In the current study, we studied the effect of a newborn larvae-specific serine protease from Trichinella spiralis (TsSp) on the host immune and inflammatory responses. A 49-kDa recombinant TsSp (rTsSp) was expressed in Escherichia coli BL21 (DE3) and purified. The cytotoxicity of rTsSp was analyzed. The immune protective effect of rTsSp was studied by using dextran sodium sulfate (DSS)-induced mouse colitis model. The result illustrated that rTsSp has no toxic effects on cells. We further demonstrated that administration of the rTsSp without the additional adjuvant before the induction of DSS-induced colitis reduced the severity of intestinal inflammation and the disease index; it suppressed macrophage infiltration, reduced TNF-α secretion, and induced IL-10 expression. Our findings suggest therapeutic potential of rTsSp on colitis by altering the effect of macrophages. Data also suggest immunotherapy with rTsSp holds promise for use as an additional strategy to positively modulate inflammatory processes involved in IBD.
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Affiliation(s)
- Shao Rong Long
- Department of Parasitology, Medical College of Zhengzhou University, Zhengzhou, China.,Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States
| | - Ruo Dan Liu
- Department of Parasitology, Medical College of Zhengzhou University, Zhengzhou, China
| | - Deepak Vijaya Kumar
- Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States
| | - Zhong Quan Wang
- Department of Parasitology, Medical College of Zhengzhou University, Zhengzhou, China
| | - Chien-Wen Su
- Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States
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12
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Tanasescu R, Tench CR, Constantinescu CS, Telford G, Singh S, Frakich N, Onion D, Auer DP, Gran B, Evangelou N, Falah Y, Ranshaw C, Cantacessi C, Jenkins TP, Pritchard DI. Hookworm Treatment for Relapsing Multiple Sclerosis: A Randomized Double-Blinded Placebo-Controlled Trial. JAMA Neurol 2021; 77:1089-1098. [PMID: 32539079 DOI: 10.1001/jamaneurol.2020.1118] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Importance Studies suggest gut worms induce immune responses that can protect against multiple sclerosis (MS). To our knowledge, there are no controlled treatment trials with helminth in MS. Objective To determine whether hookworm treatment has effects on magnetic resonance imaging (MRI) activity and T regulatory cells in relapsing MS. Design, Setting, and Participants This 9-month double-blind, randomized, placebo-controlled trial was conducted between September 2012 and March 2016 in a modified intention-to-treat population (the data were analyzed June 2018) at the University of Nottingham, Queen's Medical Centre, a single tertiary referral center. Patients aged 18 to 61 years with relapsing MS without disease-modifying treatment were recruited from the MS clinic. Seventy-three patients were screened; of these, 71 were recruited (2 ineligible/declined). Interventions Patients were randomized (1:1) to receive either 25 Necator americanus larvae transcutaneously or placebo. The MRI scans were performed monthly during months 3 to 9 and 3 months posttreatment. Main Outcomes and Measures The primary end point was the cumulative number of new/enlarging T2/new enhancing T1 lesions at month 9. The secondary end point was the percentage of cluster of differentiation (CD) 4+CD25highCD127negT regulatory cells in peripheral blood. Results Patients (mean [SD] age, 45 [9.5] years; 50 women [71%]) were randomized to receive hookworm (35 [49.3%]) or placebo (36 [50.7%]). Sixty-six patients (93.0%) completed the trial. The median cumulative numbers of new/enlarging/enhancing lesions were not significantly different between the groups by preplanned Mann-Whitney U tests, which lose power with tied data (high number of zeroactivity MRIs in the hookworm group, 18/35 [51.4%] vs 10/36 [27.8%] in the placebo group). The percentage of CD4+CD25highCD127negT cells increased at month 9 in the hookworm group (hookworm, 32 [4.4%]; placebo, 34 [3.9%]; P = .01). No patients withdrew because of adverse effects. There were no differences in adverse events between groups except more application-site skin discomfort in the hookworm group (82% vs 28%). There were 5 relapses (14.3%) in the hookworm group vs 11 (30.6%) receiving placebo. Conclusions and Relevance Treatment with hookworm was safe and well tolerated. The primary outcome did not reach significance, likely because of a low level of disease activity. Hookworm infection increased T regulatory cells, suggesting an immunobiological effect of hookworm. It appears that a living organism can precipitate immunoregulatory changes that may affect MS disease activity. Trial Registration ClinicalTrials.gov Identifier: NCT01470521.
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Affiliation(s)
- Radu Tanasescu
- Division of Clinical Neuroscience, University of Nottingham, Nottingham, England.,Department of Neurology, Nottingham University Hospitals National Health Service Trust, Nottingham, England.,Division of Clinical Neurosciences, University of Medicine and Pharmacy Carol Davila Bucharest, Bucharest, Romania.,Department of Neurology, Colentina Hospital, Bucharest, Romania
| | - Christopher R Tench
- Division of Clinical Neuroscience, University of Nottingham, Nottingham, England.,National Institute of Health Research Nottingham BRC, Nottingham, England
| | - Cris S Constantinescu
- Division of Clinical Neuroscience, University of Nottingham, Nottingham, England.,Department of Neurology, Nottingham University Hospitals National Health Service Trust, Nottingham, England
| | - Gary Telford
- Immune Regulation Research Group, University of Nottingham, Nottingham, England
| | - Sonika Singh
- Division of Clinical Neuroscience, University of Nottingham, Nottingham, England
| | - Nanci Frakich
- Division of Clinical Neuroscience, University of Nottingham, Nottingham, England
| | - David Onion
- Flow Cytometry Facilities, School of Life Sciences, University of Nottingham, Nottingham, England
| | - Dorothee P Auer
- Division of Clinical Neuroscience, University of Nottingham, Nottingham, England.,National Institute of Health Research Nottingham BRC, Nottingham, England.,Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, England
| | - Bruno Gran
- Division of Clinical Neuroscience, University of Nottingham, Nottingham, England.,Department of Neurology, Nottingham University Hospitals National Health Service Trust, Nottingham, England
| | - Nikos Evangelou
- Division of Clinical Neuroscience, University of Nottingham, Nottingham, England.,Department of Neurology, Nottingham University Hospitals National Health Service Trust, Nottingham, England
| | - Yasser Falah
- Division of Clinical Neuroscience, University of Nottingham, Nottingham, England.,Department of Neurology, Nottingham University Hospitals National Health Service Trust, Nottingham, England
| | - Colin Ranshaw
- Immune Regulation Research Group, University of Nottingham, Nottingham, England
| | - Cinzia Cantacessi
- Department of Veterinary Medicine, University of Cambridge, Cambridge, England
| | - Timothy P Jenkins
- Department of Veterinary Medicine, University of Cambridge, Cambridge, England
| | - David I Pritchard
- Immune Regulation Research Group, University of Nottingham, Nottingham, England
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13
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Mu Y, McManus DP, Hou N, Cai P. Schistosome Infection and Schistosome-Derived Products as Modulators for the Prevention and Alleviation of Immunological Disorders. Front Immunol 2021; 12:619776. [PMID: 33692793 PMCID: PMC7937812 DOI: 10.3389/fimmu.2021.619776] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 01/08/2021] [Indexed: 12/22/2022] Open
Abstract
Parasitic helminths, comprising the flatworms (tapeworms and flukes) and nematodes (roundworms), have plagued humans persistently over a considerable period of time. It is now known that the degree of exposure to these and other pathogens inversely correlates with the incidence of both T helper 1 (Th1)-mediated autoimmunity and Th2-mediated allergy. Accordingly, there has been recent increased interest in utilizing active helminth worm infections and helminth-derived products for the treatment of human autoimmune and inflammatory diseases and to alleviate disease severity. Indeed, there is an accumulating list of novel helminth derived molecules, including proteins, peptides, and microRNAs, that have been shown to exhibit therapeutic potential in a variety of disease models. Here we consider the blood-dwelling schistosome flukes, which have evolved subtle immune regulatory mechanisms that promote parasite survival but at the same time minimize host tissue immunopathology. We review and discuss the recent advances in using schistosome infection and schistosome-derived products as therapeutics to treat or mitigate human immune-related disorders, including allergic asthma, arthritis, colitis, diabetes, sepsis, cystitis, and cancer.
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Affiliation(s)
- Yi Mu
- Molecular Parasitology Laboratory, Infectious Diseases Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Donald P McManus
- Molecular Parasitology Laboratory, Infectious Diseases Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Nan Hou
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Pengfei Cai
- Molecular Parasitology Laboratory, Infectious Diseases Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
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14
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Parker W, Sarafian JT, Broverman SA, Laman JD. Between a hygiene rock and a hygienic hard place: Avoiding SARS-CoV-2 while needing environmental exposures for immunity. Evol Med Public Health 2021; 9:120-130. [PMID: 33732461 PMCID: PMC7928958 DOI: 10.1093/emph/eoab006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 02/01/2020] [Indexed: 12/13/2022] Open
Abstract
Suboptimal understanding of concepts related to hygiene by the general public, clinicians and researchers is a persistent problem in health and medicine. Although hygiene is necessary to slow or prevent deadly pandemics of infectious disease such as coronavirus disease 2019 (COVID-19), hygiene can have unwanted effects. In particular, some aspects of hygiene cause a loss of biodiversity from the human body, characterized by the almost complete removal of intestinal worms (helminths) and protists. Research spanning more than half a century documents that this loss of biodiversity results in an increased propensity for autoimmune disease, allergic disorders, probably neuropsychiatric problems and adverse reactions to infectious agents. The differences in immune function between communities with and communities without helminths have become so pronounced that the reduced lethality of severe acute respiratory syndrome coronavirus 2 in low-income countries compared to high-income countries was predicted early in the COVID-19 pandemic. This prediction, based on the maladaptive immune responses observed in many cases of COVID-19 in high-income countries, is now supported by emerging data from low-income countries. Herein, hygiene is subdivided into components involving personal choice versus components instituted by community wide systems such as sewage treatment facilities and water treatment plants. The different effects of personal hygiene and systems hygiene are described, and appropriate measures to alleviate the adverse effects of hygiene without losing the benefits of hygiene are discussed. Finally, text boxes are provided to function as stand-alone, public-domain handouts with the goal of informing the public about hygiene and suggesting solutions for biomedical researchers and policy makers. Lay Summary: Hygiene related to sewer systems and other technology can have adverse effects on immune function, and is distinct from personal hygiene practices such as hand washing and social distancing. Dealing with the drawbacks of hygiene must be undertaken without compromising the protection from infectious disease imposed by hygiene.
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Affiliation(s)
- William Parker
- Department of Surgery, Duke University Medical Center, Durham, NC, USA
| | - Joshua T Sarafian
- Department of Surgery, Duke University Medical Center, Durham, NC, USA
| | - Sherryl A Broverman
- Department of Biology and the Duke Global Health Institute, Duke University, Durham, NC, USA
| | - Jon D Laman
- Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, Groningen, The Netherlands
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15
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Metwali A, Winckler S, Urban JF, Kaplan MH, Ince MN, Elliott DE. Helminth-induced regulation of T-cell transfer colitis requires intact and regulated T cell Stat6 signaling in mice. Eur J Immunol 2020; 51:433-444. [PMID: 33067820 DOI: 10.1002/eji.201848072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 07/24/2020] [Indexed: 02/01/2023]
Abstract
Infection with parasitic worms (helminths) alters host immune responses and can inhibit pathogenic inflammation. Helminth infection promotes a strong Th2 and T regulatory response while suppressing Th1 and Th17 function. Th2 responses are largely dependent on transcriptional programs directed by Stat6-signaling. We examined the importance of intact T cell Stat6 signaling on helminth-induced suppression of murine colitis that results from T cell transfer into immune-deficient mice. Colonization with the intestinal nematode Heligmosomoides polygyrus bakeri resolves WT T cell transfer colitis. However, if the transferred T cells lack intact Stat6 then helminth exposure failed to attenuate colitis or suppress MLN T cell IFN-γ or IL17 production. Loss of Stat6 signaling resulted in decreased IL10 and increased IFN-γ co-expression by IL-17+ T cells. We also transferred T cells from mice with constitutive T cell expression of activated Stat6 (Stat6VT). These mice developed a severe eosinophilic colitis that also was not attenuated by helminth infection. These results show that T cell expression of intact but regulated Stat6 signaling is required for helminth infection-associated regulation of pathogenic intestinal inflammation.
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Affiliation(s)
- Ahmed Metwali
- Internal Medicine, Iowa City Veterans Administration Health Center, Iowa City, IA, USA.,Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, USA
| | - Sarah Winckler
- Internal Medicine, Iowa City Veterans Administration Health Center, Iowa City, IA, USA.,Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, USA
| | - Joseph F Urban
- U.S. Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, Beltsville, MD, USA
| | - Mark H Kaplan
- Department of Pediatrics, H.B. Wells Center for Pediatric Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - M Nedim Ince
- Internal Medicine, Iowa City Veterans Administration Health Center, Iowa City, IA, USA.,Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, USA
| | - David E Elliott
- Internal Medicine, Iowa City Veterans Administration Health Center, Iowa City, IA, USA.,Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, USA
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16
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Cepon-Robins TJ, Gildner TE. Old friends meet a new foe: A potential role for immune-priming parasites in mitigating COVID-19 morbidity and mortality. Evol Med Public Health 2020; 2020:234-248. [PMID: 33235797 PMCID: PMC7665448 DOI: 10.1093/emph/eoaa037] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 10/07/2020] [Indexed: 02/06/2023] Open
Abstract
The novel virus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and the associated Coronavirus Disease 2019 (COVID-19) represent a pathogen to which human beings have limited to no evolved immune response. The most severe symptoms are associated with overactive inflammatory immune responses, leading to a cytokine storm, tissue damage, and death, if not balanced and controlled. Hypotheses within Evolutionary Medicine, including the Hygiene/Old Friends Hypothesis, provide an important lens through which to understand and possibly control this overactive immune response. In this article, we explore the role that infection with soil-transmitted helminths (STHs; i.e. intestinal parasitic worms) may play in dampening SARS-CoV-2 symptoms and mitigating the worst COVID-19 outcomes. Specifically, STHs stimulate the immunosuppressive and regulatory T-helper 2 (TH2) branch of the immune system, which decreases ACE2-receptor expression (i.e. receptors SARS-CoV-2 uses to infect host cells), balances the inflammatory TH1/TH17 branches of the immune system triggered by SARS-CoV-2 infection, and reduces inflammation through the release of anti-inflammatory/regulatory cytokines. Because STHs are common and affect the most vulnerable and marginalized members of society, it is especially important to consider how these parasites may impact COVID-19 outcomes. Areas experiencing endemic STH infections are often characterized by a lack of preventative infrastructure and medical care, which may further exacerbate risk of SARS-CoV-2 infection and COVID-19 development. For this reason, we also explore biocultural factors that contribute to disease outcomes for both SARS-CoV-2 and STH infections. Biocultural and Evolutionary Medicine perspectives on COVID-19 are crucial for understanding the global impact of the disease. Lay summary: An evolutionary perspective is required to understand the global impact and various presentations of COVID-19. We consider how coinfection with soil-transmitted helminths (common parasitic worms that coevolved with humans) may suppress inflammatory immune activity, thereby potentially reducing COVID-19 disease severity. Structural and lifestyle factors shaping coinfection patterns are also discussed.
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Affiliation(s)
- Tara J Cepon-Robins
- Department of Anthropology, University of Colorado Colorado Springs, Centennial Hall 120, 1420 Austin Bluffs Parkway, Colorado Springs, CO 80918, USA
| | - Theresa E Gildner
- Department of Anthropology, Dartmouth College, Silsby Hall, 3 Tuck Drive, Hanover, NH 03755, USA
- Department of Anthropology, Washington University, Campus Box 1114, One Brookings Drive, St. Louis, MO 63130, USA
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17
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Ayelign B, Akalu Y, Teferi B, Molla MD, Shibabaw T. Helminth Induced Immunoregulation and Novel Therapeutic Avenue of Allergy. J Asthma Allergy 2020; 13:439-451. [PMID: 33116652 PMCID: PMC7548329 DOI: 10.2147/jaa.s273556] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 09/17/2020] [Indexed: 12/24/2022] Open
Abstract
Allergic diseases are increasing at an alarming rate worldwide, particularly in developed countries. In contrast, there is a decrease in the prevalence of helminthic infections and other neglected diseases. The hygiene hypothesis elaborates parasitic infection, and allergy-associated diseases have an inverse relationship. Acute helminthic infection and allergic reaction stimulate Type 2 helper cells (Th2) immune response with up-regulation of cytokines IL-4-, IL-5-, and IL-13-mediated IgE and mast cell production, as well as eosinophilia. However, people who chronically suffer from helminthic infections are demarcated through polarized Th2 resulting in alternative macrophage activation and T regulatory response. This regulatory system reduces allergy incidence in individuals that are chronically diseased through helminth. As a result, the excretory-secretory (ES) substance derived from parasites and extracellular vesicular components can be used as a novel therapeutic modality of allergy. Therefore, the aim of this review meticulously explored the link between helminth infection and allergy, and utilization of the helminth secretome for therapeutic immunomodulation.
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Affiliation(s)
- Birhanu Ayelign
- Department of Immunology and Molecular Biology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Yonas Akalu
- Department of Physiology, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Banchamlak Teferi
- Department of Clinical Pharmacy, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Meseret Derbew Molla
- Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Tewodros Shibabaw
- Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
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18
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Dawson HD, Chen C, Li RW, Bell LN, Shea-Donohue T, Kringel H, Beshah E, Hill DE, Urban JF. Molecular and metabolomic changes in the proximal colon of pigs infected with Trichuris suis. Sci Rep 2020; 10:12853. [PMID: 32732949 PMCID: PMC7393168 DOI: 10.1038/s41598-020-69462-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 07/06/2020] [Indexed: 12/14/2022] Open
Abstract
The pig whipworm Trichuris suis is important in swine production because of its negative effects on pig performance and, notably, to some humans with inflammatory bowel disease as a therapeutic agent that modulates inflammation. The proximal colon of T. suis-infected pigs exhibited general inflammation around day 21 after inoculation with infective eggs that is transcriptionally characterized by markers of type-2 immune activation, inflammation, cellular infiltration, tissue repair enzymes, pathways of oxidative stress, and altered intestinal barrier function. Prominent gene pathways involved the Th2-response, de novo cholesterol synthesis, fructose and glucose metabolism, basic amino acid metabolism, and bile acid transport. Upstream regulatory factor analysis implicated the bile acid/farnesoid X receptor in some of these processes. Metabolic analysis indicated changes in fatty acids, antioxidant capacity, biochemicals related to methylation, protein glycosylation, extracellular matrix structure, sugars, Krebs cycle intermediates, microbe-derived metabolites and altered metabolite transport. Close to 1,200 differentially expressed genes were modulated in the proximal colon of pigs with a persistent adult worm infection that was nearly 90% lower in pigs that had expelled worms. The results support a model to test diets that favorably alter the microbiome and improve host intestinal health in both pigs and humans exposed to Trichuris.
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Affiliation(s)
- Harry D Dawson
- United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, Beltsville, USA
| | - Celine Chen
- United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, Beltsville, USA
| | - Robert W Li
- Beltsville Agricultural Research Center, Animal Parasitic Diseases Laboratory, Beltsville, MD, USA
| | | | | | - Helene Kringel
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ethiopia Beshah
- United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, Beltsville, USA
| | - Dolores E Hill
- Beltsville Agricultural Research Center, Animal Parasitic Diseases Laboratory, Beltsville, MD, USA
| | - Joseph F Urban
- United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, Beltsville, USA. .,Beltsville Agricultural Research Center, Animal Parasitic Diseases Laboratory, Beltsville, MD, USA.
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19
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Impact of Helminth Infections during Pregnancy on Vaccine Immunogenicity in Gabonese Infants. Vaccines (Basel) 2020; 8:vaccines8030381. [PMID: 32664597 PMCID: PMC7563176 DOI: 10.3390/vaccines8030381] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/06/2020] [Accepted: 07/08/2020] [Indexed: 01/13/2023] Open
Abstract
Helminth infections are common in sub-Saharan Africa. Besides direct clinical effects, a bias towards a T helper type 2 (Th2) cell immune response is observed. The consequences of parasite infection during pregnancy for the mother and particularly for the fetus and the newborn can be severe and may include impaired immune response during acute infection and vaccination. Here, we present data of immune responses to vaccines given within the expanded program on immunization (EPI) of infants born to helminth infected or non-infected mothers. The study was conducted in Lambaréné and surroundings, Gabon. Maternal helminth infection was diagnosed microscopically using the Kato-Katz method for soil-transmitted helminths (STH), urine filtration for Schistosoma haematobium infections and the saponin-based method for filarial infections. Plasma antibody levels to different vaccine antigens were measured in mothers and their offspring by enzyme-linked immunosorbent assay (ELISA) at different timepoints. We found 42.3% of the mothers to be infected with at least one helminth species. Significantly lower anti-tetanus toxoid immunoglobulin (Ig) G was detected in the cord blood of infants born to helminth infected mothers. Following vaccination, immune responses of the infants to EPI vaccines were similar between the two groups at nine and 12 months. Even though infection with helminths is still common in pregnant women in Gabon, in our setting, there was no evidence seen for a substantial effect on infants’ immune responses to vaccines given as part of the EPI.
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20
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Shayesteh Z, Hosseini H, Nasiri V, Haddadi Z, Moradi N, Beikzadeh L, Sezavar M, Heidari A, Zibaei M. Evaluating the preventive and curative effects of Toxocara canis larva in Freund's complete adjuvant-induced arthritis. Parasite Immunol 2020; 42:e12760. [PMID: 32472559 DOI: 10.1111/pim.12760] [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: 07/17/2019] [Revised: 05/16/2020] [Accepted: 05/21/2020] [Indexed: 11/29/2022]
Abstract
Helminthic infection and the parallel host immune reactions are the results of a protracted dynamic co-interaction between the host and worms. An assessment of the effect of Toxocara canis infection on arthritis in rats stimulated by Freund's complete adjuvant (FCA) was the main purpose of the investigation. An arthritis model was established by the administration of 0.1 mL FCA in the palmar surface. Cytokine assessment, evaluating oedema and the use of a rheumatoid arthritis (RA) score provided evidence of the protective effects of T canis against adjuvant-induced arthritis (AIA). The cytokines TGF-β, IFN-ɣ, IL-10 and IL-17 were measured to assess the anti-inflammatory effect of T canis infection. Besides, arthritis swelling findings were evaluated in rat paws. The data showed that T canis infection significantly modulated the immune response by alleviating inflammatory cytokines and increasing TGF-β as an anti-inflammatory cytokine. Evaluations of arthritis swelling showed low severity and faster recuperation. These findings suggest that the products derived from T canis eggs might be a potential therapeutic candidate to treat autoimmune diseases like the arthritis.
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Affiliation(s)
- Zahra Shayesteh
- Department of Immunology, School of Medicine, Hamedan University of Medical Sciences, Hamedan, Iran
| | - Hamid Hosseini
- Department of Parasitology and Mycology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Vahid Nasiri
- Protozoology Laboratory, Parasitology Department, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
| | - Zeinab Haddadi
- Department of Medical Laboratory Sciences, School of Allied Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Najmeh Moradi
- Department of Immunology, School of Medicine, Hamedan University of Medical Sciences, Hamedan, Iran
| | - Leila Beikzadeh
- Department of Medical Laboratory Sciences, School of Allied Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Monireh Sezavar
- Department of Medical Laboratory Sciences, School of Allied Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Aliehsan Heidari
- Department of Parasitology and Mycology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Mohammad Zibaei
- Department of Parasitology and Mycology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
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21
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Maizels RM. Regulation of immunity and allergy by helminth parasites. Allergy 2020; 75:524-534. [PMID: 31187881 DOI: 10.1111/all.13944] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 06/04/2019] [Accepted: 06/05/2019] [Indexed: 12/26/2022]
Abstract
There is increasing interest in helminth parasite modulation of the immune system, both from the fundamental perspective of the "arms race" between host and parasite, and equally importantly, to understand if parasites offer new pathways to abate and control untoward immune responses in humans. This article reviews the epidemiological and experimental evidence for parasite down-regulation of host immunity and immunopathology, in allergy and other immune disorders, and recent progress towards defining the mechanisms and molecular mediators which parasites exploit in order to modulate their host. Among these are novel products that interfere with epithelial cell alarmins, dendritic cell activation, macrophage function and T-cell responsiveness through the promotion of an immunoregulatory environment. These modulatory effects assist parasites to establish and survive, while dampening immune reactivity to allergens, autoantigens and microbiome determinants.
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Affiliation(s)
- Rick M. Maizels
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunology and Inflammation University of Glasgow Glasgow UK
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22
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Khudhair Z, Alhallaf R, Eichenberger RM, Whan J, Kupz A, Field M, Krause L, Wilson DT, Daly NL, Giacomin P, Sotillo J, Loukas A. Gastrointestinal Helminth Infection Improves Insulin Sensitivity, Decreases Systemic Inflammation, and Alters the Composition of Gut Microbiota in Distinct Mouse Models of Type 2 Diabetes. Front Endocrinol (Lausanne) 2020; 11:606530. [PMID: 33613446 PMCID: PMC7892786 DOI: 10.3389/fendo.2020.606530] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022] Open
Abstract
Type 2 diabetes (T2D) is a major health problem and is considered one of the top 10 diseases leading to death globally. T2D has been widely associated with systemic and local inflammatory responses and with alterations in the gut microbiota. Microorganisms, including parasitic worms and gut microbes have exquisitely co-evolved with their hosts to establish an immunological interaction that is essential for the formation and maintenance of a balanced immune system, including suppression of excessive inflammation. Herein we show that both prophylactic and therapeutic infection of mice with the parasitic hookworm-like nematode, Nippostrongylus brasiliensis, significantly reduced fasting blood glucose, oral glucose tolerance and body weight gain in two different diet-induced mouse models of T2D. Helminth infection was associated with elevated type 2 immune responses including increased eosinophil numbers in the mesenteric lymph nodes, liver and adipose tissues, as well as increased expression of IL-4 and alternatively activated macrophage marker genes in adipose tissue, liver and gut. N. brasiliensis infection was also associated with significant compositional changes in the gut microbiota at both the phylum and order levels. Our findings show that N. brasiliensis infection drives changes in local and systemic immune cell populations, and that these changes are associated with a reduction in systemic and local inflammation and compositional changes in the gut microbiota which cumulatively might be responsible for the improved insulin sensitivity observed in infected mice. Our findings indicate that carefully controlled therapeutic hookworm infection in humans could be a novel approach for treating metabolic syndrome and thereby preventing T2D.
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Affiliation(s)
- Zainab Khudhair
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
| | - Rafid Alhallaf
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
| | - Ramon M. Eichenberger
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
| | - Jen Whan
- Advanced Analytical Center, James Cook University, Cairns, QLD, Australia
| | - Andreas Kupz
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
| | - Matt Field
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
- John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
| | | | - David T. Wilson
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
| | - Norelle L. Daly
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
| | - Paul Giacomin
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
| | - Javier Sotillo
- Parasitology Reference and Research Laboratory, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain
| | - Alex Loukas
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
- *Correspondence: Alex Loukas,
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Cystatin from Filarial Parasites Suppress the Clinical Symptoms and Pathology of Experimentally Induced Colitis in Mice by Inducing T-Regulatory Cells, B1-Cells, and Alternatively Activated Macrophages. Biomedicines 2019; 7:biomedicines7040085. [PMID: 31683524 PMCID: PMC6966632 DOI: 10.3390/biomedicines7040085] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 10/23/2019] [Accepted: 10/29/2019] [Indexed: 01/14/2023] Open
Abstract
Potential alternative therapeutic strategies for immune-mediated disorders are being increasingly recognized and are studied extensively. We previously reported the therapeutic potential of Brugia malayi derived recombinant cystatin (rBmaCys) in attenuating clinical symptoms of experimental colitis. The aim of this study was to elucidate the mechanisms involved in the rBmaCys-induced suppression of inflammation in the colon. Our results show that, the frequency of CD4+CD25+FoxP3+ regulatory T-cells was elevated in the colon and mesenteric lymph nodes. Similarly, the peritoneal macrophages recovered from the rBmaCys-treated colitis mice were alternatively activated and displayed reduced expression of TNF-α and IL-6. Another finding was significant increases in IgM+B1a-cells in the peritoneal cavity of mice following rBmaCys-treatment. These findings suggested that the regulatory cell network promoted by the rBmaCys in the colon and associated lymphoid tissues is important for its anti-inflammatory activity in the dextran sulfate sodium (DSS)-induced colitis mice.
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24
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Therapeutic applicability of helminths in autoimmune diseases - literature overview. GASTROENTEROLOGY REVIEW 2019; 14:168-172. [PMID: 31649786 PMCID: PMC6807663 DOI: 10.5114/pg.2019.88164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 02/14/2019] [Indexed: 11/17/2022]
Abstract
This paper presents an overview of published studies conducted on helminths – parasites of the human gastrointestinal tract. Making use of their ability for immunomodulation may lead to the introduction of effective therapies for autoimmune diseases. This paper presents chronologically attempts to treat autoimmune diseases not only of the gastrointestinal tract, but also of the nervous and endocrine systems, which have been undertaken for decades. The overview of analysed reports demonstrates that as medical knowledge on the cells and mediators participating actively in inflammatory processes accumulates, clinical trials focus on ever more specific areas concerning the pathomechanisms of autoimmune diseases. The outcomes of clinical trials conducted both on animals and humans give reasons to assume that the modification of the human intestinal microflora may be the key to fighting against these diseases.
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25
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Bergstrom BJ, Rose RK, Bellows AS. Stomach nematodes of cotton rats: parasites, commensals, or mutualists? J Mammal 2019. [DOI: 10.1093/jmammal/gyz136] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Abstract
We related presence and burden of stomach nematodes to body mass and reproductive allocation in hispid cotton rats (Sigmodon hispidus) from two long-running field studies in Virginia (1983–1984, n = 286; and 1988–1990, n = 425) and one from Georgia 1987–1989 (n = 459). Eighty percent of rats from the earlier Virginia sample were infected, with mean nematode mass of 1,311 mg. In the later samples, 23% (Virginia) and 33% (Georgia) were infected with mean nematode mass of 493 and 769 mg, respectively. Presence of nematodes was positively correlated with host body length for each sex in each sample. We used analysis of covariance to examine length-adjusted residuals for presence of nematodes and mass of nematodes for association with somatic and reproductive response variables. Both body and reproductive masses were either positively associated or not related to nematode presence in the two low-prevalence samples, and either negatively associated or not related to nematode presence in the high-prevalence sample. No relationships were detected between host mass and nematode mass per host in either sex in any sample. There was no effect of nematode presence on litter size of pregnant females, but there was a positive effect of nematode mass on litter size in Georgia. Recent theory provides several possible explanations for such neutral-to-positive effects of stomach nematodes on host fitness, including the evolution of host tolerance to the parasites, fecundity compensation by the hosts, and positive effects on host health via immune modulation.
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Affiliation(s)
| | - Robert K Rose
- Department of Biological Sciences, Old Dominion University, Norfolk, VA, USA
| | - A Scott Bellows
- Department of Biological Sciences, Old Dominion University, Norfolk, VA, USA
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26
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Suppression of Obesity by an Intestinal Helminth through Interactions with Intestinal Microbiota. Infect Immun 2019; 87:IAI.00042-19. [PMID: 30962398 PMCID: PMC6529657 DOI: 10.1128/iai.00042-19] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 03/16/2019] [Indexed: 12/11/2022] Open
Abstract
Obesity is increasingly causing lifestyle diseases in developed countries where helminthic infections are rarely seen. Here, we investigated whether an intestinal nematode, Heligmosomoides polygyrus, has a suppressive role in diet-induced obesity in mice. Infection with H. polygyrus suppressed weight gain in obese mice, which was associated with increased uncoupling protein 1 (UCP1) expression in adipocytes and a higher serum norepinephrine (NE) concentration. Blocking interactions of NE with its receptor on adipocytes resulted in the failure to prevent weight gain and to enhance UCP1 expression in obese mice infected with H. polygyrus, indicating that NE is responsible for the protective effects of H. polygyrus on obesity. In addition to sympathetic nerve-derived NE, the intestinal microbiota was involved in the increase in NE. Infection with H. polygyrus altered the composition of intestinal bacteria, and antibiotic treatment to reduce intestinal bacteria reversed the higher NE concentration, UCP1 expression, and prevention of the weight gain observed after H. polygyrus infection. Our data indicate that H. polygyrus exerts suppressive roles on obesity through modulation of microbiota that produce NE.
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27
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Milkowska K, Galbarczyk A, Jasienska G. Disgust sensitivity in relation to menstrual cycle phase in women with and without an infection. Am J Hum Biol 2019; 31:e23233. [DOI: 10.1002/ajhb.23233] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 12/10/2018] [Accepted: 02/24/2019] [Indexed: 12/20/2022] Open
Affiliation(s)
- Karolina Milkowska
- Department of Environmental Health Faculty of Health Science, Jagiellonian University Medical College Krakow Poland
| | - Andrzej Galbarczyk
- Department of Environmental Health Faculty of Health Science, Jagiellonian University Medical College Krakow Poland
| | - Grazyna Jasienska
- Department of Environmental Health Faculty of Health Science, Jagiellonian University Medical College Krakow Poland
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28
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Arroyo-López C. Helminth therapy for autism under gut-brain axis- hypothesis. Med Hypotheses 2019; 125:110-118. [PMID: 30902137 DOI: 10.1016/j.mehy.2019.02.042] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 02/18/2019] [Indexed: 12/20/2022]
Abstract
Autism is a neurodevelopmental disease included within Autism Syndrome Disorder (ASD) spectrum. ASD has been linked to a series of genes that play a role in immune response function and patients with autism, commonly suffer from immune-related comorbidities. Despite the complex pathophysiology of autism, Gut-brain axis is gaining strength in the understanding of several neurological disorders. In addition, recent publications have shown the correlation between immune dysfunctions, gut microbiota and brain with the behavioral alterations and comorbid symptoms found in autism. Gut-brain axis acts as the "second brain", in a communication network established between neural, endocrine and the immunological systems. On the other hand, Hygiene Hypothesis suggests that the increase in the incidence of autoimmune diseases in the modern world can be attributed to the decrease of exposure to infectious agents, as parasitic nematodes. Helminths induce modulatory and protective effects against several inflammatory disorders, maintaining gastrointestinal homeostasis and modulating brain functions. Helminthic therapy has been previously performed in diseases such as ulcerative colitis, Crohn's disease, diabetes, multiple sclerosis, asthma, rheumatoid arthritis, and food allergies. Considering gut-brain axis, Hygiene Hypothesis, and the modulatory effects of helminths I hypothesized that a treatment with Trichuris suis soluble products represents a feasible holistic treatment for autism, and the key for the development of novel treatments. Preclinical studies are required to test this hypothesis.
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Affiliation(s)
- Celia Arroyo-López
- Department of Pathology and Laboratory Medicine, UC Davis School of Medicine; Institute for Pediatric Regenerative Medicine and Shriners Hospitals for Children of Northern California, United States.
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29
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Tang CL, Zou JN, Zhang RH, Liu ZM, Mao CL. Helminths protect against type 1 diabetes: effects and mechanisms. Parasitol Res 2019; 118:1087-1094. [PMID: 30758662 DOI: 10.1007/s00436-019-06247-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 02/01/2019] [Indexed: 02/07/2023]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which cells of the immune system destroy pancreatic β cells, which secrete insulin. The high prevalence of T1D in developed societies may be explained by environmental changes, including lower exposure to helminths. Indeed, infection by helminths such as Schistosoma, Filaria, and Heligmosomoides polygyrus and their by-products has been reported to ameliorate or prevent the development of T1D in human and animal models. Helminths can trigger distinct immune regulatory pathways, often involving adaptive immune cells that include T helper 2 (Th2) cells and regulatory T cells (Tregs) and innate immune cells that include dendritic cells, macrophages, and invariant natural killer T cells, which may act synergistically to induce Tregs in a Toll-like receptor-dependent manner. Cytokines such as interleukin (IL)-4, IL-10, and transforming growth factor (TGF)-β also play an important role in protection from T1D. Herein, we provide a comprehensive review of the effects and mechanisms underlying protection against T1D by helminths.
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Affiliation(s)
- Chun-Lian Tang
- Wuchang Hospital affiliated to Wuhan University of Science and Technology, Wuhan, 430063, China
| | - Jie-Ning Zou
- Wuchang Hospital affiliated to Wuhan University of Science and Technology, Wuhan, 430063, China
| | - Rong-Hui Zhang
- Wuchang Hospital affiliated to Wuhan University of Science and Technology, Wuhan, 430063, China
| | - Zhi-Ming Liu
- Wuchang Hospital affiliated to Wuhan University of Science and Technology, Wuhan, 430063, China.
| | - Cun-Lan Mao
- Department of Obstetrics and Gynecology, People's Hospital of Songzi City, Songzi, 434200, Hubei, China.
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30
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Zakeri A, Hansen EP, Andersen SD, Williams AR, Nejsum P. Immunomodulation by Helminths: Intracellular Pathways and Extracellular Vesicles. Front Immunol 2018; 9:2349. [PMID: 30369927 PMCID: PMC6194161 DOI: 10.3389/fimmu.2018.02349] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Accepted: 09/21/2018] [Indexed: 12/13/2022] Open
Abstract
Helminth parasites are masters at manipulating host immune responses, using an array of sophisticated mechanisms. One of the major mechanisms enabling helminths to establish chronic infections is the targeting of pattern recognition receptors (PRRs) including toll-like receptors, C-type lectin receptors, and the inflammasome. Given the critical role of these receptors and their intracellular pathways in regulating innate inflammatory responses, and also directing adaptive immunity toward Th1 and Th2 responses, recognition of the pathways triggered and/or modulated by helminths and their products will provide detailed insights about how helminths are able to establish an immunoregulatory environment. However, helminths also target PRRs-independent mechanisms (and most likely other yet unknown mechanisms and pathways) underpinning the battery of different molecules helminths produce. Herein, the current knowledge on intracellular pathways in antigen presenting cells activated by helminth-derived biomolecules is reviewed. Furthermore, we discuss the importance of helminth-derived vesicles as a less-appreciated components released during infection, their role in activating these host intracellular pathways, and their implication in the development of new therapeutic approaches for inflammatory diseases and the possibility of designing a new generation of vaccines.
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Affiliation(s)
- Amin Zakeri
- Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Eline P. Hansen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Sidsel D. Andersen
- Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Andrew R. Williams
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Peter Nejsum
- Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
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31
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Li Y, Guan X, Liu W, Chen HL, Truscott J, Beyatli S, Metwali A, Weiner GJ, Zavazava N, Blumberg RS, Urban JF, Blazar BR, Elliott DE, Ince MN. Helminth-Induced Production of TGF-β and Suppression of Graft-versus-Host Disease Is Dependent on IL-4 Production by Host Cells. THE JOURNAL OF IMMUNOLOGY 2018; 201:2910-2922. [PMID: 30291167 DOI: 10.4049/jimmunol.1700638] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 09/07/2018] [Indexed: 02/07/2023]
Abstract
Helminths stimulate the secretion of Th2 cytokines, like IL-4, and suppress lethal graft-versus-host disease (GVHD) after bone marrow transplantation. This suppression depends on the production of immune-modulatory TGF-β and is associated with TGF-β-dependent in vivo expansion of Foxp3+ regulatory T cells (Treg). In vivo expansion of Tregs is under investigation for its potential as a therapy for GVHD. Nonetheless, the mechanism of induced and TGF-β-dependent in vivo expansion of Tregs, in a Th2 polarized environment after helminth infection, is unknown. In this study, we show that helminth-induced IL-4 production by host cells is critical to the induction and maintenance of TGF-β secretion, TGF-β-dependent expansion of Foxp3+ Tregs, and the suppression of GVHD. In mice with GVHD, the expanding donor Tregs express the Th2-driving transcription factor, GATA3, which is required for helminth-induced production of IL-4 and TGF-β. In contrast, TGF-β is not necessary for GATA3 expression by Foxp3+ Tregs or by Foxp3- CD4 T cells. Various cell types of innate or adaptive immune compartments produce high quantities of IL-4 after helminth infection. As a result, IL-4-mediated suppression of GVHD does not require invariant NKT cells of the host, a cell type known to produce IL-4 and suppress GVHD in other models. Thus, TGF-β generation, in a manner dependent on IL-4 secretion by host cells and GATA3 expression, constitutes a critical effector arm of helminthic immune modulation that promotes the in vivo expansion of Tregs and suppresses GVHD.
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Affiliation(s)
- Yue Li
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Xiaoqun Guan
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Weiren Liu
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Hung-Lin Chen
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Jamie Truscott
- Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Sonay Beyatli
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Ahmed Metwali
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - George J Weiner
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.,Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Nicholas Zavazava
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.,Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Richard S Blumberg
- Department of Internal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115
| | - Joseph F Urban
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD 20705; and
| | - Bruce R Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455
| | - David E Elliott
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.,Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - M Nedim Ince
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242; .,Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
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32
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Li Y, Liu W, Guan X, Truscott J, Creemers JW, Chen HL, Pesu M, El Abiad RG, Karacay B, Urban JF, Elliott DE, Kaplan MH, Blazar BR, Ince MN. STAT6 and Furin Are Successive Triggers for the Production of TGF-β by T Cells. THE JOURNAL OF IMMUNOLOGY 2018; 201:2612-2623. [PMID: 30266770 DOI: 10.4049/jimmunol.1700808] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 09/03/2018] [Indexed: 01/11/2023]
Abstract
Production of TGF-β by T cells is key to various aspects of immune homeostasis, with defects in this process causing or aggravating immune-mediated disorders. The molecular mechanisms that lead to TGF-β generation by T cells remain largely unknown. To address this issue, we take advantage of the fact that intestinal helminths stimulate Th2 cells besides triggering TGF-β generation by T lymphocytes and regulate immune-mediated disorders. We show that the Th2 cell-inducing transcription factor STAT6 is necessary and sufficient for the expression of TGF-β propeptide in T cells. STAT6 is also necessary for several helminth-triggered events in mice, such as TGF-β-dependent suppression of alloreactive inflammation in graft-versus-host disease. Besides STAT6, helminth-induced secretion of active TGF-β requires cleavage of propeptide by the endopeptidase furin. Thus, for the immune regulatory pathway necessary for TGF-β production by T cells, our results support a two-step model, composed of STAT6 and furin.
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Affiliation(s)
- Yue Li
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Weiren Liu
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Xiaqun Guan
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Jamie Truscott
- Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - John W Creemers
- Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, B-3000 Belgium
| | - Hung-Lin Chen
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Marko Pesu
- Immunoregulation, BioMediTech, Faculty of Medicine and Life Sciences, University of Tampere, FI-33520 Tampere, Finland.,Department of Dermatology, Tampere University Hospital, FI-33520 Tampere, Finland
| | - Rami G El Abiad
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Bahri Karacay
- Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Joseph F Urban
- Diet, Genomics and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD 20705
| | - David E Elliott
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Mark H Kaplan
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Bruce R Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455; and
| | - M Nedim Ince
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242; .,Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
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33
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The Untapped Pharmacopeic Potential of Helminths. Trends Parasitol 2018; 34:828-842. [PMID: 29954660 DOI: 10.1016/j.pt.2018.05.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 05/29/2018] [Accepted: 05/31/2018] [Indexed: 02/06/2023]
Abstract
The dramatic rise in immunological disorders that occurs with socioeconomic development is associated with alterations in microbial colonization and reduced exposure to helminths. Excretory-secretory (E/S) helminth products contain a mixture of proteins and low-molecular-weight molecules representing the primary interface between parasite and host. Research has shown great pharmacopeic potential for helminth-derived products in animal disease models and even in clinical trials. Although in its infancy, the translation of worm-derived products into therapeutics is highly promising. Here, we focus on important key aspects in the development of immunomodulatory drugs, also highlighting novel approaches that hold great promise for future development of innovative research strategies.
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34
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Feng X, Classon C, Terán G, Yang Y, Li L, Chan S, Ribacke U, Rothfuchs AG, Coquet JM, Nylén S. Atrophy of skin-draining lymph nodes predisposes for impaired immune responses to secondary infection in mice with chronic intestinal nematode infection. PLoS Pathog 2018; 14:e1007008. [PMID: 29772005 PMCID: PMC5957330 DOI: 10.1371/journal.ppat.1007008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 04/03/2018] [Indexed: 11/18/2022] Open
Abstract
Intestinal nematodes suppress immune responses in the context of allergy, gut inflammation, secondary infection and vaccination. Several mechanisms have been proposed for this suppression including alterations in Th2 cell differentiation and increased Treg cell suppressive function. In this study, we show that chronic nematode infection leads to reduced peripheral responses to vaccination because of a generalized reduction in the available responsive lymphocyte pool. We found that superficial skin-draining lymph nodes (LNs) in mice that are chronically infected with the intestinal nematode Heligmosomides polygyrus, do not reach the same cellularity as worm-free mice upon subsequent BCG infection in the skin. B cells and T cells, all declined in skin-draining LN of H. polygyrus-infected mice, resulting in LNs atrophy and altered lymphocyte composition. Importantly, anti-helminthic treatment improved lymphocyte numbers in skin-draining LN, indicating that time after de-worming is critical to regain full-scale LN cellularity. De-worming, and time for the skin LN to recover cellularity, also mended responses to Bacille Calmette-Guerin (BCG) in the LN draining the footpad injection site. Thus, our findings show that chronic nematode infection leads to a paucity of lymphocytes in peripheral lymph nodes, which acts to reduce the efficacy of immune responses at these sites.
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Affiliation(s)
- Xiaogang Feng
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
| | - Cajsa Classon
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
| | - Graciela Terán
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
| | - Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Lei Li
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Sherwin Chan
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
| | - Ulf Ribacke
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
| | | | - Jonathan M. Coquet
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
| | - Susanne Nylén
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
- * E-mail:
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35
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Zöller M. Janus-Faced Myeloid-Derived Suppressor Cell Exosomes for the Good and the Bad in Cancer and Autoimmune Disease. Front Immunol 2018; 9:137. [PMID: 29456536 PMCID: PMC5801414 DOI: 10.3389/fimmu.2018.00137] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Accepted: 01/16/2018] [Indexed: 12/22/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells originally described to hamper immune responses in chronic infections. Meanwhile, they are known to be a major obstacle in cancer immunotherapy. On the other hand, MDSC can interfere with allogeneic transplant rejection and may dampen autoreactive T cell activity. Whether MDSC-Exosomes (Exo) can cope with the dangerous and potentially therapeutic activities of MDSC is not yet fully explored. After introducing MDSC and Exo, it will be discussed, whether a blockade of MDSC-Exo could foster the efficacy of immunotherapy in cancer and mitigate tumor progression supporting activities of MDSC. It also will be outlined, whether application of native or tailored MDSC-Exo might prohibit autoimmune disease progression. These considerations are based on the steadily increasing knowledge on Exo composition, their capacity to distribute throughout the organism combined with selectivity of targeting, and the ease to tailor Exo and includes open questions that answers will facilitate optimizing protocols for a MDSC-Exo blockade in cancer as well as for strengthening their therapeutic efficacy in autoimmune disease.
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Affiliation(s)
- Margot Zöller
- Tumor Cell Biology, University Hospital of Surgery, University of Heidelberg, Heidelberg, Germany
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36
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Mendlovic F, Cruz-Rivera M, Diaz-Gandarilla JA, Flores-Torres MA, Avila G, Perfiliev M, Salazar AM, Arriaga-Pizano L, Ostrosky-Wegman P, Flisser A. Orally administered Taenia solium Calreticulin prevents experimental intestinal inflammation and is associated with a type 2 immune response. PLoS One 2017; 12:e0186510. [PMID: 29036211 PMCID: PMC5643116 DOI: 10.1371/journal.pone.0186510] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 10/03/2017] [Indexed: 01/15/2023] Open
Abstract
Intestinal helminth antigens are inducers of type 2 responses and can elicit regulatory immune responses, resulting in dampened inflammation. Several platyhelminth proteins with anti-inflammatory activity have been reported. We have identified, cloned and expressed the Taenia solium calreticulin (rTsCRT) and shown that it predominantly induces a type 2 response characterized by IgG1, IL-4 and IL-5 production in mice. Here, we report the rTsCRT anti-inflammatory activity in a well-known experimental colitis murine model. Mice were orally immunized with purified rTsCRT and colitis was induced with trinitrobenzene sulfonic acid (TNBS). Clinical signs of disease, macroscopic and microscopic tissue inflammation, cytokine production and micronuclei formation, as a marker of genotoxicity, were measured in order to assess the effect of rTsCRT immunization on experimentally induced colitis. rTsCRT administration prior to TNBS instillation significantly reduced the inflammatory parameters, including the acute phase cytokines TNF-α, IL-1β and IL-6. Dampened inflammation was associated with increased local expression of IL-13 and systemic IL-10 and TGF-β production. Genotoxic damage produced by the inflammatory response was also precluded. Our results show that oral treatment with rTsCRT prevents excessive TNBS-induced inflammation in mice and suggest that rTsCRT has immunomodulatory properties associated with the expression of type 2 and regulatory cytokines commonly observed in other helminths.
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Affiliation(s)
- Fela Mendlovic
- Departamento de Microbiologia y Parasitologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico
- Facultad de Ciencias de la Salud, Universidad Anahuac Mexico Norte, Huixquilucan, Estado de Mexico, Mexico
- * E-mail:
| | - Mayra Cruz-Rivera
- Departamento de Microbiologia y Parasitologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico
| | - Jose Alfredo Diaz-Gandarilla
- Departamento de Microbiologia y Parasitologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico
- Division Academica Multidisciplinaria de Comalcalco, Universidad Juarez Autonoma de Tabasco, Comalcalco, Tabasco, Mexico
| | - Marco Antonio Flores-Torres
- Departamento de Microbiologia y Parasitologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico
| | - Guillermina Avila
- Departamento de Microbiologia y Parasitologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico
| | - Maria Perfiliev
- Departamento de Microbiologia y Parasitologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico
| | - Ana Maria Salazar
- Departamento de Medicina Genomica y Toxicologıa Ambiental, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico
| | - Lourdes Arriaga-Pizano
- Unidad de Investigación Medica en Inmunoquimica, Hospital de Especialidades CMN "Siglo XXI", IMSS, Ciudad de Mexico, Mexico
| | - Patricia Ostrosky-Wegman
- Departamento de Medicina Genomica y Toxicologıa Ambiental, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico
| | - Ana Flisser
- Departamento de Microbiologia y Parasitologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico
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He L, Zhou S, Qi Q, Chi Y, Zhu J, Xu Z, Wang X, Hoellwarth J, Liu F, Chen X, Su C. The regulation of regulation: interleukin-10 increases CD4 + CD25 + regulatory T cells but impairs their immunosuppressive activity in murine models with schistosomiasis japonica or asthma. Immunology 2017; 153:84-96. [PMID: 28799262 DOI: 10.1111/imm.12813] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 08/02/2017] [Accepted: 08/04/2017] [Indexed: 12/13/2022] Open
Abstract
CD4+ CD25+ Foxp3+ regulatory T (Treg) cells play an important role in maintaining immune homeostasis. Interleukin-10 (IL-10), a cytokine with anti-inflammatory capacities, also has a critical role in controlling immune responses. In addition, it is well known that production of IL-10 is one of the suppression mechanisms of Treg cells. However, the action of IL-10 on Treg cells themselves remains insufficiently understood. In this study, by using a Schistosoma japonicum-infected murine model, we show that the elevated IL-10 contributed to Treg cell induction but impaired their immunosuppressive function. Our investigations further suggest that this may relate to the up-regulation of serum transforming growth factor (TGF-β) level but the decrease in membrane-bound TGF-β of Treg cells by IL-10 during S. japonicum infection. In addition, similar IL-10-mediated regulation on Treg cells was also confirmed in the murine model of asthma. In general, our findings identify a previously unrecognized opposing regulation of IL-10 on Treg cells and provide a deep insight into the precise regulation in immune responses.
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Affiliation(s)
- Lei He
- State Key Lab of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Sha Zhou
- State Key Lab of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qianqian Qi
- State Key Lab of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ying Chi
- State Key Lab of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jifeng Zhu
- State Key Lab of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhipeng Xu
- State Key Lab of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xuefeng Wang
- State Key Lab of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jason Hoellwarth
- Department of Orthopedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Feng Liu
- State Key Lab of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaojun Chen
- State Key Lab of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chuan Su
- State Key Lab of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Province Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
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Wegener Parfrey L, Jirků M, Šíma R, Jalovecká M, Sak B, Grigore K, Jirků Pomajbíková K. A benign helminth alters the host immune system and the gut microbiota in a rat model system. PLoS One 2017; 12:e0182205. [PMID: 28771620 PMCID: PMC5542714 DOI: 10.1371/journal.pone.0182205] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 07/16/2017] [Indexed: 12/26/2022] Open
Abstract
Helminths and bacteria are major players in the mammalian gut ecosystem and each influences the host immune system and health. Declines in helminth prevalence and bacterial diversity appear to play a role in the dramatic rise of immune mediated inflammatory diseases (IMIDs) in western populations. Helminths are potent modulators of immune system and their reintroduction is a promising therapeutic avenue for IMIDs. However, the introduction of helminths represents a disturbance for the host and it is important to understand the impact of helminth reintroduction on the host, including the immune system and gut microbiome. We tested the impact of a benign tapeworm, Hymenolepis diminuta, in a rat model system. We find that H. diminuta infection results in increased interleukin 10 gene expression in the beginning of the prepatent period, consistent with induction of a type 2 immune response. We also find induction of humoral immunity during the patent period, shown here by increased IgA in feces. Further, we see an immuno-modulatory effect in the small intestine and spleen in patent period, as measured by reductions in tissue immune cells. We observed shifts in microbiota community composition during the patent period (beta-diversity) in response to H. diminuta infection. However, these compositional changes appear to be minor; they occur within families and genera common to both treatment groups. There was no change in alpha diversity. Hymenolepis diminuta is a promising model for helminth therapy because it establishes long-term, stable colonization in rats and modulates the immune system without causing bacterial dysbiosis. These results suggest that the goal of engineering a therapeutic helminth that can safely manipulate the mammalian immune system without disrupting the rest of the gut ecosystem is in reach.
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Affiliation(s)
- Laura Wegener Parfrey
- Departments of Botany and Zoology, University of British Columbia, Vancouver, Canada.,Integrated Microbial Biodiversity Program, Canadian Institute for Advanced Research, Toronto, Canada
| | - Milan Jirků
- Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, České Budějovice, Czech Republic
| | - Radek Šíma
- Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, České Budějovice, Czech Republic
| | - Marie Jalovecká
- Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, České Budějovice, Czech Republic
| | - Bohumil Sak
- Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, České Budějovice, Czech Republic
| | - Karina Grigore
- Departments of Botany and Zoology, University of British Columbia, Vancouver, Canada
| | - Kateřina Jirků Pomajbíková
- Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, České Budějovice, Czech Republic
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Pan W, Hao WT, Shen YJ, Li XY, Wang YJ, Sun FF, Yin JH, Zhang J, Tang RX, Cao JP, Zheng KY. The excretory-secretory products of Echinococcus granulosus protoscoleces directly regulate the differentiation of B10, B17 and Th17 cells. Parasit Vectors 2017; 10:348. [PMID: 28732522 PMCID: PMC5520350 DOI: 10.1186/s13071-017-2263-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 06/26/2017] [Indexed: 12/18/2022] Open
Abstract
Background Excretory-secretory products (ESPs) released by helminths are well-known to regulate T cell responses in the host. However, their direct influence in the differentiation of naïve T cells, and especially B cells, remains largely unknown. This study investigated the effects of Echinococcus granulosus protoscoleces ESPs (EgPSC-ESPs) on the differentiation of IL-10-producing B cells (B10), IL-17A-producing B cells (B17) and Th17 cells. Methods BALB/c mice injected with EgPSC were used to evaluate the in vivo profiles of B10, B17 and Th17 cells. In vitro purified CD19+ B and naïve CD4+ T cells were cultured in the presence of native, heat-inactivated or periodate-treated EgPSC-ESPs, and the differentiation of these cell subsets were compared. Results In contrast to the control group, infected mice showed higher frequencies of B10, B17 and Th17 cells, and higher levels of IL-10 and IL-17A in the sera. Interestingly, B17 cells were first identified to express CD19+CD1dhigh. In vitro, B cells cultured with native ESPs exhibited a higher percentage of B10 cells but lower percentage of B17 and Th17 cells compared to the PBS group. Moreover, the relative expression of IL-10 and IL-17A mRNA were consistent with the altered frequencies. However, ESPs subjected to heat-inactivation or periodate treatment exhibited an inverse effect on the induction of these cell subsets. Conclusions Our findings indicate that ESPs released by EgPSC can directly regulate the differentiation of B10, B17 and Th17 cells, which appear to be heat-labile and carbohydrate-dependent. Electronic supplementary material The online version of this article (doi:10.1186/s13071-017-2263-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Wei Pan
- Jiangsu Key Laboratory of Immunity and Metabolism; Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu Province, China.,National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention; Key Laboratory of Parasite and Vector Biology, Ministry of Health, Shanghai, China
| | - Wen-Ting Hao
- Jiangsu Key Laboratory of Immunity and Metabolism; Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Yu-Juan Shen
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention; Key Laboratory of Parasite and Vector Biology, Ministry of Health, Shanghai, China
| | - Xiang-Yang Li
- Jiangsu Key Laboratory of Immunity and Metabolism; Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Yan-Juan Wang
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention; Key Laboratory of Parasite and Vector Biology, Ministry of Health, Shanghai, China
| | - Fen-Fen Sun
- Jiangsu Key Laboratory of Immunity and Metabolism; Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Jian-Hai Yin
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention; Key Laboratory of Parasite and Vector Biology, Ministry of Health, Shanghai, China
| | - Jing Zhang
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention; Key Laboratory of Parasite and Vector Biology, Ministry of Health, Shanghai, China
| | - Ren-Xian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism; Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Jian-Ping Cao
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention; Key Laboratory of Parasite and Vector Biology, Ministry of Health, Shanghai, China.
| | - Kui-Yang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism; Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu Province, China.
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40
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Varyani F, Fleming JO, Maizels RM. Helminths in the gastrointestinal tract as modulators of immunity and pathology. Am J Physiol Gastrointest Liver Physiol 2017; 312:G537-G549. [PMID: 28302598 PMCID: PMC5495915 DOI: 10.1152/ajpgi.00024.2017] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 03/06/2017] [Accepted: 03/12/2017] [Indexed: 01/31/2023]
Abstract
Helminth parasites are highly prevalent in many low- and middle-income countries, in which inflammatory bowel disease and other immunopathologies are less frequent than in the developed world. Many of the most common helminths establish themselves in the gastrointestinal tract and can exert counter-inflammatory influences on the host immune system. For these reasons, interest has arisen as to how parasites may ameliorate intestinal inflammation and whether these organisms, or products they release, could offer future therapies for immune disorders. In this review, we discuss interactions between helminth parasites and the mucosal immune system, as well as the progress being made toward identifying mechanisms and molecular mediators through which it may be possible to attenuate pathology in the intestinal tract.
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Affiliation(s)
- Fumi Varyani
- 1Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom; ,2Edinburgh Clinical Academic Track, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom; and
| | - John O. Fleming
- 3Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Rick M. Maizels
- 1Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom;
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41
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Anthelmintic Therapy Modifies the Systemic and Mycobacterial Antigen-Stimulated Cytokine Profile in Helminth-Latent Mycobacterium tuberculosis Coinfection. Infect Immun 2017; 85:IAI.00973-16. [PMID: 28167672 DOI: 10.1128/iai.00973-16] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 02/01/2017] [Indexed: 11/20/2022] Open
Abstract
Helminth infections are known to modulate cytokine responses in latent tuberculosis (LTB). However, very few studies have examined whether this modulation is reversible upon anthelmintic therapy. We measured the systemic and mycobacterial (TB) antigen-stimulated levels of type 1, type 2, type 17, and regulatory cytokines in individuals with LTB and with or without coexistent Strongyloides stercoralis infection before and after anthelmintic therapy. Our data reveal that individuals with LTB and coexistent S. stercoralis infection have significantly lower levels of systemic and TB antigen-stimulated type 1 (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-2 [IL-2]) and type 17 (IL-17A and/or IL-17F) cytokines and significantly higher levels of systemic but not TB antigen-stimulated type 2 (IL-4 and IL-5) and regulatory (transforming growth factor beta [TGF-β]) cytokines. Anthelmintic therapy resulted in significantly increased systemic levels of type 1 and/or type 17 cytokines and in significantly decreased systemic levels of type 2 and regulatory (IL-10 and TGF-β) cytokines. In addition, anthelmintic therapy resulted in significantly increased TB antigen-stimulated levels of type 1 cytokines only. Our data therefore confirm that the modulation of systemic and TB antigen-stimulated cytokine responses in S. stercoralis-LTB coinfection is reversible (for the most part) by anthelmintic treatment.
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42
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Tao L, Reese TA. Making Mouse Models That Reflect Human Immune Responses. Trends Immunol 2017; 38:181-193. [PMID: 28161189 DOI: 10.1016/j.it.2016.12.007] [Citation(s) in RCA: 138] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 12/19/2016] [Accepted: 12/30/2016] [Indexed: 02/08/2023]
Abstract
Humans are infected with a variety of acute and chronic pathogens over the course of their lives, and pathogen-driven selection has shaped the immune system of humans. The same is likely true for mice. However, laboratory mice we use for most biomedical studies are bred in ultra-hygienic environments, and are kept free of specific pathogens. We review recent studies that indicate that pathogen infections are important for the basal level of activation and the function of the immune system. Consideration of these environmental exposures of both humans and mice can potentially improve mouse models of human disease.
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Affiliation(s)
- Lili Tao
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Tiffany A Reese
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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43
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Terrazas C, de Dios Ruiz-Rosado J, Amici SA, Jablonski KA, Martinez-Saucedo D, Webb LM, Cortado H, Robledo-Avila F, Oghumu S, Satoskar AR, Rodriguez-Sosa M, Terrazas LI, Guerau-de-Arellano M, Partida-Sánchez S. Helminth-induced Ly6C hi monocyte-derived alternatively activated macrophages suppress experimental autoimmune encephalomyelitis. Sci Rep 2017; 7:40814. [PMID: 28094319 PMCID: PMC5240103 DOI: 10.1038/srep40814] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 12/12/2016] [Indexed: 12/14/2022] Open
Abstract
Helminths cause chronic infections and affect the immune response to unrelated inflammatory diseases. Although helminths have been used therapeutically to ameliorate inflammatory conditions, their anti-inflammatory properties are poorly understood. Alternatively activated macrophages (AAMϕs) have been suggested as the anti-inflammatory effector cells during helminth infections. Here, we define the origin of AAMϕs during infection with Taenia crassiceps, and their disease-modulating activity on the Experimental Autoimmune Encephalomyelitis (EAE). Our data show two distinct populations of AAMϕs, based on the expression of PD-L1 and PD-L2 molecules, resulting upon T. crassiceps infection. Adoptive transfer of Ly6C+ monocytes gave rise to PD-L1+/PD-L2+, but not PD-L1+/PD-L2- cells in T. crassiceps-infected mice, demonstrating that the PD-L1+/PD-L2+ subpopulation of AAMϕs originates from blood monocytes. Furthermore, adoptive transfer of PD-L1+/PD-L2+ AAMϕs into EAE induced mice reduced disease incidence, delayed disease onset, and diminished the clinical disability, indicating the critical role of these cells in the regulation of autoimmune disorders.
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Affiliation(s)
- Cesar Terrazas
- Department of Pathology, The Ohio State University, Columbus, OH 43221, USA
| | - Juan de Dios Ruiz-Rosado
- Center for Microbial Pathogenesis, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA
| | - Stephanie A. Amici
- School of Health and Rehabilitation Sciences, Medical Laboratory Science Division, The Ohio State University, Columbus, Ohio, USA
| | - Kyle A. Jablonski
- School of Health and Rehabilitation Sciences, Medical Laboratory Science Division, The Ohio State University, Columbus, Ohio, USA
| | - Diana Martinez-Saucedo
- Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, UNAM, Tlalnepantla, MEX, Mexico
| | - Lindsay M. Webb
- School of Health and Rehabilitation Sciences, Medical Laboratory Science Division, The Ohio State University, Columbus, Ohio, USA
- Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio, USA
| | - Hanna Cortado
- Center for Microbial Pathogenesis, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA
| | - Frank Robledo-Avila
- Center for Microbial Pathogenesis, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA
| | - Steve Oghumu
- Environmental Health Sciences, College of Public Health, Ohio State University, Columbus, OH, USA
| | - Abhay R. Satoskar
- Department of Pathology, The Ohio State University, Columbus, OH 43221, USA
| | - Miriam Rodriguez-Sosa
- Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, UNAM, Tlalnepantla, MEX, Mexico
| | - Luis I. Terrazas
- Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, UNAM, Tlalnepantla, MEX, Mexico
| | - Mireia Guerau-de-Arellano
- School of Health and Rehabilitation Sciences, Medical Laboratory Science Division, The Ohio State University, Columbus, Ohio, USA
| | - Santiago Partida-Sánchez
- Center for Microbial Pathogenesis, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, USA
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44
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Lund ME, Greer J, Dixit A, Alvarado R, McCauley-Winter P, To J, Tanaka A, Hutchinson AT, Robinson MW, Simpson AM, O'Brien BA, Dalton JP, Donnelly S. A parasite-derived 68-mer peptide ameliorates autoimmune disease in murine models of Type 1 diabetes and multiple sclerosis. Sci Rep 2016; 6:37789. [PMID: 27883079 PMCID: PMC5121616 DOI: 10.1038/srep37789] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 11/02/2016] [Indexed: 12/16/2022] Open
Abstract
Helminth parasites secrete molecules that potently modulate the immune responses of their hosts and, therefore, have potential for the treatment of immune-mediated human diseases. FhHDM-1, a 68-mer peptide secreted by the helminth parasite Fasciola hepatica, ameliorated disease in two different murine models of autoimmunity, type 1 diabetes and relapsing-remitting immune-mediated demyelination. Unexpectedly, FhHDM-1 treatment did not affect the proliferation of auto-antigen specific T cells or their production of cytokines. However, in both conditions, the reduction in clinical symptoms was associated with the absence of immune cell infiltrates in the target organ (islets and the brain tissue). Furthermore, after parenteral administration, the FhHDM-1 peptide interacted with macrophages and reduced their capacity to secrete pro-inflammatory cytokines, such as TNF and IL-6. We propose this inhibition of innate pro-inflammatory immune responses, which are central to the initiation of autoimmunity in both diseases, prevented the trafficking of autoreactive lymphocytes from the periphery to the site of autoimmunity (as opposed to directly modulating their function per se), and thus prevented tissue destruction. The ability of FhHDM-1 to modulate macrophage function, combined with its efficacy in disease prevention in multiple models, suggests that FhHDM-1 has considerable potential as a treatment for autoimmune diseases.
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Affiliation(s)
- Maria E Lund
- The School of Life Sciences, University of Technology Sydney, New South Wales, Australia
| | - Judith Greer
- The University of Queensland, UQ Centre for Clinical Research, Brisbane, Queensland, Australia
| | - Aakanksha Dixit
- The University of Queensland, UQ Centre for Clinical Research, Brisbane, Queensland, Australia
| | - Raquel Alvarado
- The School of Life Sciences, University of Technology Sydney, New South Wales, Australia
| | | | - Joyce To
- The School of Life Sciences, University of Technology Sydney, New South Wales, Australia
| | - Akane Tanaka
- The School of Life Sciences, University of Technology Sydney, New South Wales, Australia
| | - Andrew T Hutchinson
- The School of Life Sciences, University of Technology Sydney, New South Wales, Australia.,The Centre for Health Technology, University of Technology Sydney, New South Wales, Australia
| | - Mark W Robinson
- Medical Biology Center, School of Biological Sciences, Queen's University, Belfast, Northern Ireland, United Kingdom
| | - Ann M Simpson
- The School of Life Sciences, University of Technology Sydney, New South Wales, Australia.,The Centre for Health Technology, University of Technology Sydney, New South Wales, Australia
| | - Bronwyn A O'Brien
- The School of Life Sciences, University of Technology Sydney, New South Wales, Australia.,The Centre for Health Technology, University of Technology Sydney, New South Wales, Australia
| | - John P Dalton
- Medical Biology Center, School of Biological Sciences, Queen's University, Belfast, Northern Ireland, United Kingdom
| | - Sheila Donnelly
- The School of Life Sciences, University of Technology Sydney, New South Wales, Australia
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45
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Laan LC, Williams AR, Stavenhagen K, Giera M, Kooij G, Vlasakov I, Kalay H, Kringel H, Nejsum P, Thamsborg SM, Wuhrer M, Dijkstra CD, Cummings RD, van Die I. The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells. FASEB J 2016; 31:719-731. [PMID: 27806992 DOI: 10.1096/fj.201600841r] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 10/24/2016] [Indexed: 12/11/2022]
Abstract
Clinical trials have shown that administration of the nematode Trichuris suis can be beneficial in treating various immune disorders. To provide insight into the mechanisms by which this worm suppresses inflammatory responses, an active component was purified from T. suis soluble products (TsSPs) that suppress---- TNF and IL-12 secretion from LPS-activated human dendritic cells (DCs). Analysis by liquid chromatography tandem mass spectrometry identified this compound as prostaglandin (PG)E2. The purified compound showed similar properties compared with TsSPs and commercial PGE2 in modulating LPS-induced expression of many cytokines and chemokines and in modulating Rab7B and P2RX7 expression in human DCs. Furthermore, the TsSP-induced reduction of TNF secretion from DCs is reversed by receptor antagonists for EP2 and EP4, indicating PGE2 action. T. suis secretes extremely high amounts of PGE2 (45-90 ng/mg protein) within their excretory/secretory products but few related lipid mediators as established by metabololipidomic analysis. Culture of T. suis with several cyclooxygenase (COX) inhibitors that inhibit mammalian prostaglandin synthesis affected the worm's motility but did not inhibit PGE2 secretion, suggesting that the worms can synthesize PGE2 via a COX-independent pathway. We conclude that T. suis secretes PGE2 to suppress proinflammatory responses in human DCs, thereby modulating the host's immune response.-Laan, L. C., Williams, A. R., Stavenhagen, K., Giera, M., Kooij, G., Vlasakov, I., Kalay, H., Kringel, H., Nejsum, P., Thamsborg, S. M., Wuhrer, M., Dijkstra, C. D., Cummings, R. D., van Die, I. The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells.
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Affiliation(s)
- Lisa C Laan
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, Vrije Universiteit Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Andrew R Williams
- Section for Parasitology, Health, and Development, Department of Veterinary Disease Biology, University of Copenhagen, Denmark
| | - Kathrin Stavenhagen
- Division of BioAnalytical Chemistry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.,Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Martin Giera
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Gijs Kooij
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, Vrije Universiteit Medical Center Amsterdam, Amsterdam, The Netherlands.,Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; and
| | - Iliyan Vlasakov
- Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; and
| | - Hakan Kalay
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, Vrije Universiteit Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Helene Kringel
- Section for Parasitology, Health, and Development, Department of Veterinary Disease Biology, University of Copenhagen, Denmark
| | - Peter Nejsum
- Section for Parasitology, Health, and Development, Department of Veterinary Disease Biology, University of Copenhagen, Denmark
| | - Stig M Thamsborg
- Section for Parasitology, Health, and Development, Department of Veterinary Disease Biology, University of Copenhagen, Denmark
| | - Manfred Wuhrer
- Division of BioAnalytical Chemistry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.,Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Christine D Dijkstra
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, Vrije Universiteit Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Richard D Cummings
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School Center for Glycosciences, Boston, Massachusetts, USA
| | - Irma van Die
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, Vrije Universiteit Medical Center Amsterdam, Amsterdam, The Netherlands;
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46
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Briggs N, Weatherhead J, Sastry KJ, Hotez PJ. The Hygiene Hypothesis and Its Inconvenient Truths about Helminth Infections. PLoS Negl Trop Dis 2016; 10:e0004944. [PMID: 27632204 PMCID: PMC5025185 DOI: 10.1371/journal.pntd.0004944] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Current iterations of the hygiene hypothesis suggest an adaptive role for helminth parasites in shaping the proper maturation of the immune system. However, aspects of this hypothesis are based on assumptions that may not fully account for realities about human helminth infections. Such realities include evidence of causal associations between helminth infections and asthma or inflammatory bowel disease as well as the fact that helminth infections remain widespread in the United States, especially among populations at greatest risk for inflammatory and autoimmune diseases.
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Affiliation(s)
- Neima Briggs
- Department of Immunology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America
- The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, United States of America
- Sabin Vaccine Institute and Texas Children’s Hospital Center for Vaccine Development, Departments of Pediatrics and Molecular Virology and Microbiology, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Jill Weatherhead
- Sabin Vaccine Institute and Texas Children’s Hospital Center for Vaccine Development, Departments of Pediatrics and Molecular Virology and Microbiology, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - K. Jagannadha Sastry
- Department of Immunology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America
- The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, United States of America
| | - Peter J. Hotez
- Sabin Vaccine Institute and Texas Children’s Hospital Center for Vaccine Development, Departments of Pediatrics and Molecular Virology and Microbiology, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- James A Baker III Institute for Public Policy, Rice University, Houston, Texas, United States of America
- Department of Biology, Baylor University, Waco, Texas, United States of America
- Scowcroft Institute of International Affairs, Bush School of Government and Public Service, Texas A&M University, College Station, Texas, United States of America
- * E-mail:
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47
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Abstract
Many immune-mediated diseases like inflammatory bowel disease, multiple sclerosis, type 1 diabetes, asthma, and food allergy appeared to have increased in frequency in developed countries in the latter part of the twentieth century. Reports from less developed countries suggest that the "epidemic" of immune-mediated diseases now is spreading into these regions as well. The "hygiene hypothesis" was developed to partly explain this phenomenon. It has been proposed that modern-day sanitary living has altered our exposure to organisms that provided protection from these diseases in the past. Alternations in the composition of our intestinal flora and fauna could play a role. Helminths are a group of worm-like parasitic organisms that have adapted to live in various regions of their hosts. Epidemiological and some clinical data suggest that these organisms can protect people from developing immune-mediated diseases. Animal experimentation has shown that helminths stimulate the production of regulatory cytokines, activate regulatory T cells, and induce regulatory dendritic cells and macrophages. This could be the mechanism by which they protect the host from these diseases. Early clinical studies also suggest that helminths may prove useful for treating immunological diseases. More sophisticated clinical studies are underway, testing live helminth agents as therapeutic agents. Also, a strong effort is ongoing to discover the agents produced by helminths that modulate host immune responses with an eye on developing new, highly effective immune modulatory therapeutic agent.
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Affiliation(s)
- Joel V Weinstock
- Division of Gastroenterology (Box 233), Tufts Medical Center, 800 Washington St., Boston, MA, 02111, USA.
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48
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Helminth-Tuberculosis Co-infection: An Immunologic Perspective. Trends Immunol 2016; 37:597-607. [PMID: 27501916 DOI: 10.1016/j.it.2016.07.005] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 07/13/2016] [Accepted: 07/14/2016] [Indexed: 01/15/2023]
Abstract
Over 2 billion people worldwide are infected with helminths (worms). Similarly, infection with Mycobacterium tuberculosis (Mtb) occurs in over a third of the world's population, often with a great degree of geographical overlap with helminth infection. Interestingly, the responses induced by the extracellular helminths and those induced by the intracellular Mtb are often mutually antagonistic and, as a consequence, can result in impaired (or cross-regulated) host responses to either of the infecting pathogens. In this review, we outline the nature of the immune responses induced by infections with helminths and tuberculosis (TB) and then provide data from both experimental models and human studies that illustrate how the immune response engendered by helminth parasites modulates Mtb-specific responses in helminth-TB coinfection.
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49
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Maizels RM, McSorley HJ. Regulation of the host immune system by helminth parasites. J Allergy Clin Immunol 2016; 138:666-675. [PMID: 27476889 PMCID: PMC5010150 DOI: 10.1016/j.jaci.2016.07.007] [Citation(s) in RCA: 363] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 07/25/2016] [Accepted: 07/25/2016] [Indexed: 01/01/2023]
Abstract
Helminth parasite infections are associated with a battery of immunomodulatory mechanisms that affect all facets of the host immune response to ensure their persistence within the host. This broad-spectrum modulation of host immunity has intended and unintended consequences, both advantageous and disadvantageous. Thus the host can benefit from suppression of collateral damage during parasite infection and from reduced allergic, autoimmune, and inflammatory reactions. However, helminth infection can also be detrimental in reducing vaccine responses, increasing susceptibility to coinfection and potentially reducing tumor immunosurveillance. In this review we will summarize the panoply of immunomodulatory mechanisms used by helminths, their potential utility in human disease, and prospective areas of future research.
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Affiliation(s)
- Rick M Maizels
- Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
| | - Henry J McSorley
- Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom
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50
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Abegunde AT, Muhammad BH, Bhatti O, Ali T. Environmental risk factors for inflammatory bowel diseases: Evidence based literature review. World J Gastroenterol 2016; 22:6296-6317. [PMID: 27468219 PMCID: PMC4945988 DOI: 10.3748/wjg.v22.i27.6296] [Citation(s) in RCA: 136] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 05/19/2016] [Accepted: 06/28/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: Advances in genetics and immunology have contributed to the current understanding of the pathogenesis of inflammatory bowel diseases (IBD).
METHODS: The current opinion on the pathogenesis of IBD suggests that genetically susceptible individuals develop intolerance to dysregulated gut microflora (dysbiosis) and chronic inflammation develops as a result of environmental insults. Environmental exposures are innumerable with varying effects during the life course of individuals with IBD. Studying the relationship between environmental factors and IBD may provide the missing link to increasing our understanding of the etiology and increased incidence of IBD in recent years with implications for prevention, diagnosis, and treatment. Environmental factors are heterogeneous and genetic predisposition, immune dysregulation, or dysbiosis do not lead to the development of IBD in isolation.
RESULTS: Current challenges in the study of environmental factors and IBD are how to effectively translate promising results from experimental studies to humans in order to develop models that incorporate the complex interactions between the environment, genetics, immunology, and gut microbiota, and limited high quality interventional studies assessing the effect of modifying environmental factors on the natural history and patient outcomes in IBD.
CONCLUSION: This article critically reviews the current evidence on environmental risk factors for IBD and proposes directions for future research.
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