|
1
|
Pazmiño FA, Parra-Muñoz M, Saavedra CH, Muvdi-Arenas S, Ovalle-Bracho C, Echeverry MC. Mucosal leishmaniasis is associated with the Leishmania RNA virus and inappropriate cutaneous leishmaniasis treatment. PLoS One 2025; 20:e0317221. [PMID: 39854299 PMCID: PMC11759362 DOI: 10.1371/journal.pone.0317221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 12/23/2024] [Indexed: 01/26/2025] Open
Abstract
BACKGROUND Mucosal leishmaniasis (ML) is a severe clinical form of leishmaniasis that is characterized by the destruction of the nasal and/or the oral mucosae and appears as a late complication in 5% to 10% of cutaneous leishmaniasis (CL) cases produced by species belonging to Leishmania (Viannia) subgenus. Some strains of Leishmania spp. carry an RNA virus known as Leishmania RNA virus (LRV) that may contribute to the appearance of ML. METHODS To examine the role of LRV type 1 (LRV1) as a risk factor associated with ML, a retrospective case-control study involving 103 patients was conducted. Cases were defined as patients with ML (n = 33), and controls corresponded to patients with CL and without mucosal lesions (n = 70). Clinical data were recorded from the patient's medical records. Cryopreserved biopsies were used to detect LRV1 and identify Leishmania species. RESULTS The frequency of LRV1 in the 103 patients was 16.5% (95% CI,10.4-25.12) being higher in samples from cases [33.33% (95% CI,18.89-51.76) than from controls [8.57% (95% CI, 3.82-18.10)]. L. (V.) braziliensis was identified in 63.6% of cases and 55.7% of the controls. Multivariate logistic regression indicated that infection with Leishmania spp. carrying LRV1 (OR = 6.30; 95% CI,1.52-26.10, p = 0.011) acts as risk factors for ML occurrence, while the completed treatment for the cutaneous event decreases the risk of ML (OR = 0.039; 95% CI, 0.01-0.12, p < 0.0001). CONCLUSIONS Our data support the association between LRV1 and ML occurrence and emphasize the effect of completed treatment for CL in preventing ML.
Collapse
Affiliation(s)
- Fredy A. Pazmiño
- Departamento de Salud Pública, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia
| | - Marcela Parra-Muñoz
- Departamento de Salud Pública, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia
| | - Carlos H. Saavedra
- Departamento de Medicina, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia
| | - Sandra Muvdi-Arenas
- Hospital Universitario Centro Dermatológico Federico Lleras Acosta, Bogotá, Colombia
| | | | - María C. Echeverry
- Departamento de Salud Pública, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia
| |
Collapse
|
|
2
|
Oliveira IBN, Nunes RV, Leite VRMC, Araújo CF, Silveira MB, Pinto SA, Lamounier LA, Borges CL, Martins E, Porto IDOP, Gomes RS, Ribeiro-Dias F. Single-nucleotide polymorphisms in genes associated with the vitamin D pathway related to clinical and therapeutic outcomes of American tegumentary leishmaniasis. Front Cell Infect Microbiol 2025; 14:1487255. [PMID: 39844838 PMCID: PMC11750871 DOI: 10.3389/fcimb.2024.1487255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 12/10/2024] [Indexed: 01/24/2025] Open
Abstract
Background The vitamin D pathway contributes to the microbicidal activity of macrophages against Leishmania infection. In addition to induction of this pathway, interferon-gamma (IFNγ), interleukin (IL)-15, and IL32γ are part of a network of pro-inflammatory cytokines. The aim of this study was to evaluate single-nucleotide polymorphisms (SNPs) in the components of the vitamin D pathway and associated cytokine genes that could be related to resistance or susceptibility to American tegumentary leishmaniasis (ATL). Methods The expressions of IFNG, IL15, IL32, CYP27B1, VDR, and other pro-inflammatory cytokines TNF, IL6, and IL17 genes were evaluated using real-time polymerase chain reaction (qPCR) in lesions of patients with localized cutaneous leishmaniasis (LCL) or mucosal leishmaniasis (ML). SNP genotypes/alleles (in IL15, IL32, CYP27B1, and VDR) were evaluated by TaqMan PCR assays using DNA from the blood of patients and healthy individuals. Serum vitamin D levels were determined by chemiluminescence. Results Vitamin D pathway-associated genes were expressed in cutaneous as well as mucosal lesions. IFNG, IL6, and IL17 were more highly expressed in ML than in LCL. In contrast, IL32γ/CYP27B1/VDR mRNAs were mainly correlated in LCL, and IL32γ in ML makes strong connections with all cytokines. The SNP IL32 rs1555001 was less frequent in patients with ML. In addition, some SNPs appear to influence the VDR and CYP27B1 (IL15 rs10519613 and IL15 rs3775597) and IL6 (VDR rs7975232) expressions in LCL and the IL17 expression in ML (IL15 rs3775597). Gene expression was also correlated with clinical parameters, such as number of lesions (CYP27B1 mRNA) and treatment failure (VDR mRNA). In addition, one SNP was associated with treatment failure in ML (VDR rs7975232). Conclusions Our findings suggested that some SNPs in the vitamin D pathway-associated genes can be related to resistance and therapeutic outcomes of ATL. They are promising candidates that need to be further evaluated to understand their biological effects in the control or immunopathogenesis of ATL.
Collapse
Affiliation(s)
- Iara Barreto Neves Oliveira
- Laboratório de Imunidade Natural (LIN), Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | - Ramon Vieira Nunes
- Laboratório de Imunidade Natural (LIN), Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | | | - Camila Freire Araújo
- Department of Infectious Diseases, Hospital de Doenças Tropicais Dr. Anuar Auad, Goiânia, Goiás, Brazil
| | - Murilo Barros Silveira
- Laboratório de Imunidade Natural (LIN), Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | - Sebastião Alves Pinto
- Department of Anatomopathology, Instituto Goiano de Oncologia e Hematologia (INGOH), Goiânia, Goiás, Brazil
| | | | - Clayton Luiz Borges
- Laboratório de Biologia Molecular (LBM), Instituto de Ciências Biológicas, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | - Edésio Martins
- Department of Morphofunctional Axis, Universidade de Rio Verde, Goiânia, Goiás, Brazil
| | | | - Rodrigo Saar Gomes
- Laboratório de Imunidade Natural (LIN), Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| | - Fátima Ribeiro-Dias
- Laboratório de Imunidade Natural (LIN), Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Goiás, Brazil
| |
Collapse
|
|
3
|
Sarmadi M, Bagherian Z, Ahmadi-Soleimani SM, Rezaiemanesh MR, Khodamoradi F, Rahimi S, Azizi H. Environmental health risk factors and cutaneous leishmaniasis (CL): A case-control study in northeastern Iran. J Vector Borne Dis 2023; 60:372-381. [PMID: 38174514 DOI: 10.4103/0972-9062.374236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2024] Open
Abstract
Background & objectives Cutaneous leishmaniasis (CL) is one of the main causes of vector-born diseases in younger population. To evaluate the association of environmental health factors on the odds of CL incidence, a case-control study was conducted in northeastern Iran. Methods This study was conducted within 2020-2021 based on individual and household data from a tertiary referral center. Cases were patients diagnosed with CL by PCR method; controls were selected among the patients' relatives, and information was obtained from a health registry system. Demographic and socioeconomic data of 1871 subjects, included age, sex, household information and environmental health factors. Multivariable models with environmental factors in various conditions and CL were separately fit by univariate and mixed multiple unconditional logistic regression. Results Participants included 617 cases (mean [SD] age, 13.62[13.72] years; 58.20% male) and 1264 controls (mean [SD] age, 16.45[15.44] years; 50.40% male). Results revealed that the use of well-water sources compared to surface water is significantly associated with CL (odds ratio [OR]=0.204; 95%CI, 0.13-0.33;P<0.001). Muddy houses, ruined buildings or wastelands and stagnant water, canals and rivers near the houses were also associated with CL (OR=3.85; 95%CI, 1.66-8.89; P=.002; OR=2.47; 95%CI, 1.76-3.47; P<.001). Besides, existence of pine tree was found to be a risk factor (OR=3.25; 95%CI, 2.12-4.99; P<.001) and similarly for the use of waste collection system (OR=4.43; 95%CI, 3.32-7.51; P<.001). Interpretation & conclusion Environmental factors related to houses were significantly associated with CL and may represent the modifiable risk factors of CL disease.
Collapse
Affiliation(s)
- Mohammad Sarmadi
- Department of Environmental Health Engineering, School of Health; Health Sciences Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Zahra Bagherian
- Student Research Committee, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - S Mohammad Ahmadi-Soleimani
- Health Sciences Research Center; Department of Physiology, School of Medicine, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Mohammad Reza Rezaiemanesh
- Health Sciences Research Center; Department of Laboratory Sciences, School of Paramedical Sciences, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Farzad Khodamoradi
- Department of Biostatistics and Epidemiology, School of Public Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Sajjad Rahimi
- Department of Environmental Health Engineering, School of Health; Health Sciences Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Hakim Azizi
- Department of Medical Parasitology, School of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| |
Collapse
|
|
4
|
Aquino RCADE, Barros BRS, Silva GAS, Sousa GFDE, Souza EBDE, Silva DRC, Nascimento AVDO, Sá IWADE, Lima ELSDE, Silva BO, Lima LPODE, Vieira AM, Barbosa Neto AG, Marcos BFS, Silva AJD, Oliveira THADE, Carvalho BM, Muniz MTC, Freitas ACDE, Campelo Júnior EB, Melo CMLDE. Healthcare workers exposed to COVID-19 patients present an inflammatory status and Th2/Th17/Th22 immune profile: findings from before vaccine application in Brazil. AN ACAD BRAS CIENC 2023; 95:e20220502. [PMID: 37255169 DOI: 10.1590/0001-3765202320220502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/30/2022] [Indexed: 06/01/2023] Open
Abstract
Healthcare workers present an increased risk of contagion for the SARS-CoV-2 virus due to their labor exposure. Here, we describe the clinical, laboratory, and immunological characteristics of healthcare workers, before vaccine application, exposed to SARS-CoV-2-infected patients. We collected sociodemographic, clinical, and laboratory information from 50 professionals who worked during the COVID-19 pandemic at the Clinical Hospital of the Northwest in Brazil. The results showed that most workers are women, over 50 years old, and worked as nursing technicians. Approximately 56% of workers were positive for a previous infection by RT-PCR and/or anti-SARS-CoV-2-immunoglobulin tests. Increased levels of hematocrit, neutrophils, NK lymphocytes, and fibrinogen, were found in positive healthcare workers, suggesting a light inflammatory status. The immunological findings showed an increase in IL-17 production and a Th2/Th17/Th22 profile followed by high serology for anti-SARS-CoV-2 IgM and IgG. Those data reveal the importance of studies with healthcare workers to investigate if the continuous exposition to the virus may result in chronic activation of the immune system and/or pulmonary inflammation in this target group.
Collapse
Affiliation(s)
- Rodrigo Cesar A DE Aquino
- Federal University of Pernambuco, Laboratory of Immunological and Antitumor Analysis, Department of Antibiotics, Bioscience Center, Av. Prof. Artur de Sá, s/n, Cidade Universitária, 50740-525 Recife, PE, Brazil
- Federal University of Pernambuco, Keizo Asami Immunopathology Laboratory Institute (iLIKA), Avenida Professor Moraes Rego, 1235, Cidade Universitária, 50670-901 Recife, PE, Brazil
| | - Bárbara Rafaela S Barros
- Federal University of Pernambuco, Laboratory of Immunological and Antitumor Analysis, Department of Antibiotics, Bioscience Center, Av. Prof. Artur de Sá, s/n, Cidade Universitária, 50740-525 Recife, PE, Brazil
- Federal University of Pernambuco, Keizo Asami Immunopathology Laboratory Institute (iLIKA), Avenida Professor Moraes Rego, 1235, Cidade Universitária, 50670-901 Recife, PE, Brazil
| | - Guilherme Antonio S Silva
- Federal University of Pernambuco, Laboratory of Immunological and Antitumor Analysis, Department of Antibiotics, Bioscience Center, Av. Prof. Artur de Sá, s/n, Cidade Universitária, 50740-525 Recife, PE, Brazil
- Federal University of Pernambuco, Keizo Asami Immunopathology Laboratory Institute (iLIKA), Avenida Professor Moraes Rego, 1235, Cidade Universitária, 50670-901 Recife, PE, Brazil
| | - Georon F DE Sousa
- Federal University of Pernambuco, Laboratory of Immunological and Antitumor Analysis, Department of Antibiotics, Bioscience Center, Av. Prof. Artur de Sá, s/n, Cidade Universitária, 50740-525 Recife, PE, Brazil
- Federal University of Pernambuco, Keizo Asami Immunopathology Laboratory Institute (iLIKA), Avenida Professor Moraes Rego, 1235, Cidade Universitária, 50670-901 Recife, PE, Brazil
| | - Edson B DE Souza
- Federal University of Pernambuco, Clinical Hospital, Avenida Professor Moraes Rego, 1235, Cidade Universitária, 50670-901 Recife, PE, Brazil
| | - Dyego R C Silva
- Federal University of Pernambuco, Clinical Hospital, Avenida Professor Moraes Rego, 1235, Cidade Universitária, 50670-901 Recife, PE, Brazil
| | - Arione V DO Nascimento
- Federal University of Pernambuco, Clinical Hospital, Avenida Professor Moraes Rego, 1235, Cidade Universitária, 50670-901 Recife, PE, Brazil
| | - Igor W A DE Sá
- Federal University of Pernambuco, Clinical Hospital, Avenida Professor Moraes Rego, 1235, Cidade Universitária, 50670-901 Recife, PE, Brazil
| | - Elker L S DE Lima
- University of Pernambuco, Institute of Biological Sciences, Rua Arnóbio Marquês, 310, Santo Amaro, 50100-130 Recife, PE, Brazil
| | - Bárbara O Silva
- University of Pernambuco, Institute of Biological Sciences, Rua Arnóbio Marquês, 310, Santo Amaro, 50100-130 Recife, PE, Brazil
| | - Luísa P O DE Lima
- University of Pernambuco, Institute of Biological Sciences, Rua Arnóbio Marquês, 310, Santo Amaro, 50100-130 Recife, PE, Brazil
| | - Amanda M Vieira
- University of Pernambuco, Institute of Biological Sciences, Rua Arnóbio Marquês, 310, Santo Amaro, 50100-130 Recife, PE, Brazil
| | - Adauto G Barbosa Neto
- University of Pernambuco, Institute of Biological Sciences, Rua Arnóbio Marquês, 310, Santo Amaro, 50100-130 Recife, PE, Brazil
| | - Bianca F São Marcos
- Federal University of Pernambuco, Laboratory of Molecular Studies and Experimental Therapy, Department of Genetics, Bioscience Center, Avenida Reitor Joaquim Amazonas, s/n, Cidade Universitária, 50740-570 Recife, PE, Brazil
| | - Anna Jéssica D Silva
- Federal University of Pernambuco, Laboratory of Molecular Studies and Experimental Therapy, Department of Genetics, Bioscience Center, Avenida Reitor Joaquim Amazonas, s/n, Cidade Universitária, 50740-570 Recife, PE, Brazil
| | - Talita Helena Araújo DE Oliveira
- Federal University of Pernambuco, Laboratory of Molecular Studies and Experimental Therapy, Department of Genetics, Bioscience Center, Avenida Reitor Joaquim Amazonas, s/n, Cidade Universitária, 50740-570 Recife, PE, Brazil
| | - Bruno M Carvalho
- University of Pernambuco, Institute of Biological Sciences, Rua Arnóbio Marquês, 310, Santo Amaro, 50100-130 Recife, PE, Brazil
| | - Maria Tereza C Muniz
- University of Pernambuco, Institute of Biological Sciences, Rua Arnóbio Marquês, 310, Santo Amaro, 50100-130 Recife, PE, Brazil
| | - Antonio Carlos DE Freitas
- Federal University of Pernambuco, Laboratory of Molecular Studies and Experimental Therapy, Department of Genetics, Bioscience Center, Avenida Reitor Joaquim Amazonas, s/n, Cidade Universitária, 50740-570 Recife, PE, Brazil
| | - Evônio B Campelo Júnior
- Federal University of Pernambuco, Clinical Hospital, Avenida Professor Moraes Rego, 1235, Cidade Universitária, 50670-901 Recife, PE, Brazil
| | - Cristiane M L DE Melo
- Federal University of Pernambuco, Laboratory of Immunological and Antitumor Analysis, Department of Antibiotics, Bioscience Center, Av. Prof. Artur de Sá, s/n, Cidade Universitária, 50740-525 Recife, PE, Brazil
- Federal University of Pernambuco, Keizo Asami Immunopathology Laboratory Institute (iLIKA), Avenida Professor Moraes Rego, 1235, Cidade Universitária, 50670-901 Recife, PE, Brazil
| |
Collapse
|
|
5
|
Ademola SA, Bamikole OJ, Amodu OK. Is TNF alpha a mediator in the co-existence of malaria and type 2 diabetes in a malaria endemic population? Front Immunol 2023; 14:1028303. [PMID: 37215099 PMCID: PMC10196125 DOI: 10.3389/fimmu.2023.1028303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 04/25/2023] [Indexed: 05/24/2023] Open
Abstract
Malaria remains a disease of public health importance globally, especially in sub-Saharan Africa. Malaria deaths reduced globally steadily between 2000-2019, however there was a 10% increase in 2020 due to disruptions in medical service during the COVID-19 pandemic. Globally, about 96% of malaria deaths occurred in 29 countries; out of which, four countries (Nigeria, the Democratic Republic of the Congo, the Niger, and the United Republic of Tanzania) accounted for just over half of the malaria deaths. Nigeria leads the four countries with the highest malaria deaths (accounting for 31% globally). Parallelly, sub-Saharan Africa is faced with a rise in the incidence of Type 2 diabetes (T2D). Until recently, T2D was a disease of adulthood and old age. However, this is changing as T2D in children and adolescents is becoming an increasingly important public health problem. Nigeria has been reported to have the highest burden of diabetes in Africa with a prevalence of 5.77% in the country. Several studies conducted in the last decade investigating the interaction between malaria and T2D in developing countries have led to the emergence of the intra-uterine hypothesis. The hypothesis has arisen as a possible explanation for the rise of T2D in malaria endemic areas; malaria in pregnancy could lead to intra-uterine stress which could contribute to low birth weight and may be a potential cause of T2D later in life. Hence, previous, and continuous exposure to malaria infection leads to a higher risk of T2D. Current and emerging evidence suggests that an inflammation-mediated link exists between malaria and eventual T2D emergence. The inflammatory process thus, is an important link for the co-existence of malaria and T2D because these two diseases are inflammatory-related. A key feature of T2D is systemic inflammation, characterized by the upregulation of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) which leads to impaired insulin signaling. Malaria infection is an inflammatory disease in which TNF-α also plays a major role. TNF-α plays an important role in the pathogenesis and development of malaria and T2D. We therefore hypothesize that TNF-α is an important link in the increasing co-existence of T2D.
Collapse
|
|
6
|
Campello CP, Lima ELS, Fernandes RSM, Lemos CAA, Muniz MTC. Genetic polymorphisms of TNF-α, IL-6, and IL-10 in female elderly patients with chronic temporomandibular disorder pain. SPECIAL CARE IN DENTISTRY 2023; 43:144-151. [PMID: 35849847 DOI: 10.1111/scd.12757] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 11/30/2022]
Abstract
AIM To verify the association of the TNF-α, IL-6, and IL-10 polymorphisms with chronic temporomandibular disorder pain development in female elderly patients. METHODS Participants were evaluated according to Diagnostic Criteria for Temporomandibular Disorders. The genomic DNA was extracted from blood according to the Salting Out method followed by a quantification using the NanoDrop spectrophotometer. The -308G/A TNF-α polymorphism analysis was performed by the polymerase chain reaction-restriction fragment length polymorphism technique, the determination of -174G/C IL-6 polymorphism was performed by polymerase chain reaction, and the evaluation of the -1082A/G IL-10 polymorphism was carried out by polymerase chain reaction- allele-specific amplification. Data were analyzed using the BioEstat 5.3 software. RESULTS The -308G/A TNF-α polymorphism showed a significant difference when genotypes of cases with chronic temporomandibular disorder pain and controls were compared (p = .025). There was a lack of association regarding the -174G/C IL-6 polymorphism (p = .286) however, a positive association between the -1082A/G IL-10 polymorphism with chronic temporomandibular disorder was observed (p = .020). CONCLUSION The analyzed data of elderly subjects support the possible involvement of the GA genotype of the -308G/A TNF-α and the AA genotype of the -1082A/G IL-10 polymorphisms in the pathogenesis of chronic temporomandibular disorder pain.
Collapse
Affiliation(s)
- Camilla Porto Campello
- MSc in Speech Sciences, PhD in Biotechnology in Health at Northeast Biotechnology Network- RENORBIO/UFRPE, Laboratory of Molecular Biology, Oswaldo Cruz University Hospital, Recife, Brazil
| | - Elker Lene Santos Lima
- PhD in Biotechnology in Health, Postdoctoral Researcher in Health Sciences at Faculty of Medical Sciences, University of Pernambuco-UPE, Laboratory of Molecular Biology, Oswaldo Cruz University Hospital, Recife, Brazil
| | - Renata Silva Melo Fernandes
- Associate Professor at Department of Prosthesis and Maxillofacial Surgery, Federal University of Pernambuco-UFPE, Recife, Brazil
| | - Cleidiel Aparecido Araújo Lemos
- Associate Professor at Department of Dentistry, Federal University of Juiz de Fora-UFJF, Governador Valadares, Minas Gerais, Brazil
| | - Maria Tereza Cartaxo Muniz
- Associate Professor at Institute of Biological Sciences, University of Pernambuco-UPE, Head of Laboratory of Molecular Biology, Oswaldo Cruz University Hospital, Recife, Brazil
| |
Collapse
|
|
7
|
Single nucleotide polymorphisms in genes involved in immune responses and outcome of tegumentary leishmaniasis. Acta Trop 2022; 235:106660. [PMID: 35988820 DOI: 10.1016/j.actatropica.2022.106660] [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: 05/04/2022] [Revised: 08/15/2022] [Accepted: 08/17/2022] [Indexed: 11/24/2022]
Abstract
Leishmaniases are neglected tropical diseases with a broad clinical spectrum. Tegumentary leishmaniasis (TL) is a disease caused by different Leishmania species, transmitted by phlebotomine sand flies and distributed worldwide. TL can present a cutaneous (CL) or mucocutaneous (MCL) clinical form depending on factors inherent to the parasite, the host and the vector. Polymorphisms in the immune response genes are host genetic factors that influence the pathogenesis or control of leishmaniasis. Single nucleotide polymorphisms (SNPs) in immune genes have been evaluated in several countries where leishmaniasis is endemic. In this review, we report studies on SNPs in several immune genes that might be associated with susceptibility or resistance to TL. We summarize studies from around the world and in Brazil, highlight the difficulties of these studies and future analyses needed to enhance our knowledge regarding host genetic factors in TL. Understanding the genetic characteristics of the host that facilitate resistance or susceptibility to leishmaniasis can contribute to the development of immunotherapy schedules for this disease. The current treatment methods are toxic, and no human vaccine is available.
Collapse
|
|
8
|
Human genetic polymorphism and Leishmaniasis. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2022; 98:105203. [PMID: 34990851 DOI: 10.1016/j.meegid.2021.105203] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 12/27/2021] [Accepted: 12/30/2021] [Indexed: 01/03/2023]
Abstract
Leishmaniasis is a disease of the subtropical and tropical spheres of the earth and has various clinical manifestations. The different form of leishmaniasis includes cutaneous leishmaniasis, mucocutaneous leishmaniasis, most lethal visceral leishmaniasis and PKDL form. These different forms depend on many factors such as parasite and vector species, geographical, environmental conditions and population ethnicity. Host genetic factors have been widely investigated for their role in developing the disease in various infections. There are several reports on associations or resistance between candidate gene polymorphisms and the risk and outcome of Leishmania infection. Polymorphism in genes involved in both innate and adaptive immune systems, as well as genes of metabolic processes contributes to disease manifestation. The wide availability and advancement of molecular techniques permits to exploration of hereditary factors related to leishmaniasis. Many candidate gene studies were conducted on family-based and population to identify novel biomarkers for understanding disease pathogenesis pathways and possible drug targets. This comprehensive review presents an update on various human genes polymorphism that influence the outcome of different forms of Leishmania infection in endemic regions of the world. Various electronic databases were searched systematically for relevant publications and thoroughly analyzed. Most of the candidate gene studies were found with discrepancies in findings. Genetic and functional studies with adequate power are needed to validate the contribution of host genes in susceptibility or resistance towards Leishmania infection and understanding pathogenesis.
Collapse
|
|
9
|
Santiago AM, da Silva Graça Amoras E, Queiroz MAF, da Silva Conde SRS, Cayres-Vallinoto IMV, Ishak R, Vallinoto ACR. TNFA -308G>A and IL10 -1082A>G polymorphisms seem to be predictive biomarkers of chronic HCV infection. BMC Infect Dis 2021; 21:1133. [PMID: 34732154 PMCID: PMC8567538 DOI: 10.1186/s12879-021-06835-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 11/01/2021] [Indexed: 12/21/2022] Open
Abstract
Background Genetic changes may induce dysregulated cytokine production and affect the progression of the chronic disease caused by the hepacivirus C (HCV) because the balance of pro- and anti-inflammatory cytokines determines the outcome of infection. This study evaluated the TNFA -308G>A and IL10 -1082A>G polymorphisms in the susceptibility and progress of chronic hepatitis C. Method The study included 101 samples from patients with chronic hepatitis C and 300 samples from healthy donors. Polymorphisms were typed by real-time PCR and were analyzed for associations with histopathological parameters (according to METAVIR classification) and HCV viral load. Results The polymorphic genotype for the TNFA -308G>A variant was not present in the group of patients with chronic hepatitis C and its absence could be associated with protection against HCV infection (p = 0.0477). Patients with the polymorphic genotype of the IL10 -1082A>G polymorphism had higher HCV viral load than wild-type patients (p = 0.0428). Neither polymorphism was associated with different levels of necroinflammatory activity or fibrosis scores. Conclusion Our results suggest the polymorphic genotype at TNFA -308G>A as protective against chronic HCV infection, and the polymorphic genotype at the IL10 -1082A>G variant associated with higher HCV viral load. Further studies must be performed in order to confirm these associations.
Collapse
Affiliation(s)
- Angélica Menezes Santiago
- Laboratory of Virology, Institute of Biological Sciences, Federal University of Pará (Universidade Federal Do Pará - UFPA), Belém, Pará, Brazil.,Graduate Program in Virology, Evandro Chagas Institute/SVS/MS, Ananindeua, Pará, Brazil
| | - Ednelza da Silva Graça Amoras
- Laboratory of Virology, Institute of Biological Sciences, Federal University of Pará (Universidade Federal Do Pará - UFPA), Belém, Pará, Brazil
| | - Maria Alice Freitas Queiroz
- Laboratory of Virology, Institute of Biological Sciences, Federal University of Pará (Universidade Federal Do Pará - UFPA), Belém, Pará, Brazil
| | - Simone Regina Souza da Silva Conde
- João de Barros Barreto Hospital, Federal University of Pará (Universidade Federal do Pará - UFPA), Belém, Pará, Brazil.,School of Medicine, Institute of Health Sciences, Federal University of Pará (Universidade Federal Do Pará - UFPA), Belém, Pará, Brazil
| | | | - Ricardo Ishak
- Laboratory of Virology, Institute of Biological Sciences, Federal University of Pará (Universidade Federal Do Pará - UFPA), Belém, Pará, Brazil
| | - Antonio Carlos Rosário Vallinoto
- Laboratory of Virology, Institute of Biological Sciences, Federal University of Pará (Universidade Federal Do Pará - UFPA), Belém, Pará, Brazil.
| |
Collapse
|
|
10
|
Barroso DH, Nóbrega ODT, de Araújo CN, Freire GSM, Martins SS, Rodrigues BC, Gomes CM, Sampaio RNR. The Presence of Leishmania braziliensis DNA in the Nasal Mucosa of Cutaneous Leishmaniasis Patients and the Search for Possible Clinical and Immunological Patterns of Disease Progression: A Cross Sectional Study. Front Cell Infect Microbiol 2021; 11:744163. [PMID: 34722337 PMCID: PMC8551912 DOI: 10.3389/fcimb.2021.744163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 09/28/2021] [Indexed: 11/15/2022] Open
Abstract
Leishmania braziliensis is the most important causal agent of American tegumentary leishmaniasis (ATL), and 3 to 5% of patients develop mucosal lesions. The mechanisms related to parasite and host immune interactions and the parasite life cycle that lead to dissemination to the mucosa are poorly understood. We aimed to detect L. braziliensis DNA in the nasal mucosa of cutaneous leishmaniasis (CL) patients with early mucous dissemination and to relate those findings to specific inflammatory responses. Nasal swabs were collected from patients with the cutaneous form of ATL. L. braziliensis DNA was investigated using TaqMan-based real-time PCR. The levels of serum cytokines (IL-12, IL-6, TNF-α, IL-10, IL-1β and IL-8) were measured by a multiplex cytometric array. A Poisson regression model was used to test prevalence ratios (PRs) and multivariate interactions of clinical and laboratory characteristics. Of the 79 CL patients, 24 (30%) had L. braziliensis DNA in the nasal mucosa. In the multivariate model, parasite DNA presence in mucosa was associated with a reduction in IL-12 levels (PR = 0.440; p=0.034), increased IL-6 levels (PR = 1.001; p=0.002) and a higher number of affected body segments (PR = 1.65; p<0.001). In this study, we observed a higher rate of early dissemination to the nasal mucosa than what was previously described. We suggest that an enhanced Th1 profile characterized by higher IL-12 is important for preventing dissemination of L. braziliensis to the mucosa. Further evaluation of parasite-related interactions with the host immunological response is necessary to elucidate the dissemination mechanisms of Leishmania.
Collapse
Affiliation(s)
- Daniel Holanda Barroso
- Programa de Pós-Graduação em Ciências Médicas, Faculdade de Medicina, Universidade de Brasília (UnB), Brasília, Brazil.,Hospital Universitário de Brasília, Universidade de Brasília, Brasília, Brazil.,Laboratório de Dermatomicologia da Faculdade de Medicina, Universidade de Brasília, Brasília, Brazil
| | - Otávio de Toledo Nóbrega
- Programa de Pós-Graduação em Ciências Médicas, Faculdade de Medicina, Universidade de Brasília (UnB), Brasília, Brazil.,Pós-Graduação de Ciências da Saúde da Faculdade de Ciências Saúde, Universidade de Brasília, Brasília, Brazil
| | - Carla Nunes de Araújo
- Programa de Pós-Graduação em Ciências Médicas, Faculdade de Medicina, Universidade de Brasília (UnB), Brasília, Brazil
| | | | - Sofia Sales Martins
- Hospital Universitário de Brasília, Universidade de Brasília, Brasília, Brazil.,Pós-Graduação de Ciências da Saúde da Faculdade de Ciências Saúde, Universidade de Brasília, Brasília, Brazil
| | - Bruna Côrtes Rodrigues
- Programa de Pós-Graduação em Ciências Médicas, Faculdade de Medicina, Universidade de Brasília (UnB), Brasília, Brazil.,Hospital Universitário de Brasília, Universidade de Brasília, Brasília, Brazil
| | - Ciro Martins Gomes
- Programa de Pós-Graduação em Ciências Médicas, Faculdade de Medicina, Universidade de Brasília (UnB), Brasília, Brazil.,Hospital Universitário de Brasília, Universidade de Brasília, Brasília, Brazil.,Laboratório de Dermatomicologia da Faculdade de Medicina, Universidade de Brasília, Brasília, Brazil.,Programa de Pós-Graduação em Medicina Tropical, Faculdade de Medicina, Universidade de Brasília (UnB), Brasília, Brazil
| | - Raimunda Nonata Ribeiro Sampaio
- Programa de Pós-Graduação em Ciências Médicas, Faculdade de Medicina, Universidade de Brasília (UnB), Brasília, Brazil.,Hospital Universitário de Brasília, Universidade de Brasília, Brasília, Brazil.,Laboratório de Dermatomicologia da Faculdade de Medicina, Universidade de Brasília, Brasília, Brazil.,Pós-Graduação de Ciências da Saúde da Faculdade de Ciências Saúde, Universidade de Brasília, Brasília, Brazil
| |
Collapse
|
|
11
|
Castellucci LC, Almeida L, Cherlin S, Fakiola M, Francis RW, Carvalho EM, Santos da Hora A, do Lago TS, Figueiredo AB, Cavalcanti CM, Alves NS, Morais KLP, Teixeira-Carvalho A, Dutra WO, Gollob KJ, Cordell HJ, Blackwell JM. A Genome-wide Association Study Identifies SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, and KRT80 As Risk Loci Contributing to Cutaneous Leishmaniasis in Brazil. Clin Infect Dis 2021; 72:e515-e525. [PMID: 32830257 PMCID: PMC8130031 DOI: 10.1093/cid/ciaa1230] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Our goal was to identify genetic risk factors for cutaneous leishmaniasis (CL) caused by Leishmania braziliensis. METHODS Genotyping 2066 CL cases and 2046 controls using Illumina HumanCoreExomeBeadChips provided data for 4 498 586 imputed single-nucleotide variants (SNVs). A genome-wide association study (GWAS) using linear mixed models took account of genetic diversity/ethnicity/admixture. Post-GWAS positional, expression quantitative trait locus (eQTL) and chromatin interaction mapping was performed in Functional Mapping and Annotation (FUMA). Transcriptional data were compared between lesions and normal skin, and cytokines measured using flow cytometry and Bioplex assay. RESULTS Positional mapping identified 32 genomic loci associated with CL, none achieving genome-wide significance (P < 5 × 10-8). Lead SNVs at 23 loci occurred at protein coding or noncoding RNA genes, 15 with eQTLs for functionally relevant cells/tissues and/or showing differential expression in lesions. Of these, the 6 most plausible genetic risk loci were SERPINB10 (Pimputed_1000G = 2.67 × 10-6), CRLF3 (Pimputed_1000G = 5.12 × 10-6), STX7 (Pimputed_1000G = 6.06 × 10-6), KRT80 (Pimputed_1000G = 6.58 × 10-6), LAMP3 (Pimputed_1000G = 6.54 × 10-6), and IFNG-AS1 (Pimputed_1000G = 1.32 × 10-5). LAMP3 (Padjusted = 9.25 × 10-12; +6-fold), STX7 (Padjusted = 7.62 × 10-3; +1.3-fold), and CRLF3 (Padjusted = 9.19 × 10-9; +1.97-fold) were expressed more highly in CL biopsies compared to normal skin; KRT80 (Padjusted = 3.07 × 10-8; -3-fold) was lower. Multiple cis-eQTLs across SERPINB10 mapped to chromatin interaction regions of transcriptional/enhancer activity in neutrophils, monocytes, B cells, and hematopoietic stem cells. Those at IFNG-AS1 mapped to transcriptional/enhancer regions in T, natural killer, and B cells. The percentage of peripheral blood CD3+ T cells making antigen-specific interferon-γ differed significantly by IFNG-AS1 genotype. CONCLUSIONS This first GWAS for CL identified multiple genetic risk loci including a novel lead to understanding CL pathogenesis through regulation of interferon-γ by IFNG antisense RNA 1.
Collapse
Affiliation(s)
- Léa C Castellucci
- National Institute of Science and Technology in Tropical Diseases, Brazil
- Federal University of Bahia, Salvador, Brazil
| | - Lucas Almeida
- National Institute of Science and Technology in Tropical Diseases, Brazil
- Federal University of Bahia, Salvador, Brazil
| | - Svetlana Cherlin
- Population Health Sciences Institute, Newcastle University, Newcastle-Upon-Tyne, United Kingdom
| | - Michaela Fakiola
- National Institute of Molecular Genetics “Romeo ed Enrica Invernizzi,” Milan, Italy
| | - Richard W Francis
- Telethon Kids Institute, University of Western Australia, Nedlands, Australia
| | - Edgar M Carvalho
- National Institute of Science and Technology in Tropical Diseases, Brazil
| | | | | | - Amanda B Figueiredo
- International Center for Research, AC Camargo Cancer Center, São Paulo, Brazil
| | - Clara M Cavalcanti
- International Center for Research, AC Camargo Cancer Center, São Paulo, Brazil
| | - Natalia S Alves
- International Center for Research, AC Camargo Cancer Center, São Paulo, Brazil
| | - Katia L P Morais
- International Center for Research, AC Camargo Cancer Center, São Paulo, Brazil
| | | | - Walderez O Dutra
- National Institute of Science and Technology in Tropical Diseases, Brazil
- Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Kenneth J Gollob
- National Institute of Science and Technology in Tropical Diseases, Brazil
- International Center for Research, AC Camargo Cancer Center, São Paulo, Brazil
- Núcleo de Ensino e Pesquisa, Instituto Mario Penna, Belo Horizonte, Brazil
| | - Heather J Cordell
- Population Health Sciences Institute, Newcastle University, Newcastle-Upon-Tyne, United Kingdom
| | - Jenefer M Blackwell
- Telethon Kids Institute, University of Western Australia, Nedlands, Australia
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| |
Collapse
|
|
12
|
Lera-Nonose DSSL, De Oliveira LF, Brustolin A, Santos TS, Oyama J, Ramos-Milaré ÁCFH, Terron-Monich MDS, Demarchi IG, Neto QADL, Teixeira JJV, Lonardoni MVC. Genetic variations in the human immune system influence susceptibility to tegumentary leishmaniasis: a systematic review and meta-analysis. Expert Rev Clin Immunol 2021; 17:513-537. [PMID: 33749481 DOI: 10.1080/1744666x.2021.1906650] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
OBJECTIVES The outcomes of tegumentary leishmaniasis (TL) rely on a complex interaction between the host immune system and the parasite. This study assessed the influence of polymorphisms in immune-related genes on TL. METHODS Web of Science, Scopus, PubMed, and Embase databases were searched systemically. The meta-analysis used a retrospective model in examining alleles, heterozygotes, and homozygotes. A quality assessment and an analysis of cumulative evidence were performed. RESULTS A total of 29 genes (encoding for cytokines, chemokines, and other immune receptors) and 84 polymorphisms were analyzed. The IL-1β_rs16944 (OR = 1.341, p = 0.003), TNF-α_rs1800629 (OR = 3.804, p = 0.004), MIF_rs755622 (OR = 3.357, p = 0.001), and INF- γ_rs243056 (OR = 1.670, p = 0.028) polymorphisms were speculated as risk factor for TL. They decrease the expression of the corresponding genes crucial for TL control. The quality assessment score was approximately 50%, suggesting the need for a clear method and polymorphism characterization for further comparison. The relevant risk of bias and other considerations resulted in low and moderate cumulative evidence confidence. CONCLUSIONS IL-1β_rs16944, TNF-α_rs1800629, MIF_rs755622, and INF-γ_rs2430561 polymorphisms were speculated as risk factor for TL, corroborating that IL-1β, TNF-α, INF-γ, and MIF are involved in the TL pathogenesis.
Collapse
Affiliation(s)
- Daniele Stéfanie Sara Lopes Lera-Nonose
- Graduate Program in Health Sciences, Universidade Estadual De Maringá, Maringá, Paraná, Brazil.,Department of Clinical Analysis and Biomedicine- Laboratory of Leishmaniasis, Universidade Estadual De Maringá, Maringá, Paraná, Brazil
| | | | - Aline Brustolin
- Graduate Program in Health Sciences, Universidade Estadual De Maringá, Maringá, Paraná, Brazil
| | - Thais Silva Santos
- Graduate Program in Bioscience and Physiopathology, Universidade Estadual De Maringá, Maringá, Paraná, Brazil
| | - Jully Oyama
- Graduate Program in Bioscience and Physiopathology, Universidade Estadual De Maringá, Maringá, Paraná, Brazil
| | - Áquila Carolina Fernandes Herculano Ramos-Milaré
- Graduate Program in Health Sciences, Universidade Estadual De Maringá, Maringá, Paraná, Brazil.,Department of Clinical Analysis and Biomedicine- Laboratory of Leishmaniasis, Universidade Estadual De Maringá, Maringá, Paraná, Brazil
| | - Mariana De Souza Terron-Monich
- Graduate Program in Health Sciences, Universidade Estadual De Maringá, Maringá, Paraná, Brazil.,Department of Basic Science-Laboratory of Immunogenetics, Universidade Estadual De Maringá, Maringá, Paraná, Brazil
| | - Izabel Galhardo Demarchi
- Graduate Program in Health Sciences, Universidade Estadual De Maringá, Maringá, Paraná, Brazil.,Department of Clinical Analysis, Universidade Federal De Santa Catarina, Roberto Sampaio Gonzaga Street, Campus Reitor João David Ferreira Lima, Florianópolis, Santa Catarina, Brazil
| | - Quirino Alves De Lima Neto
- Department of Basic Science-Laboratory of Immunogenetics, Universidade Estadual De Maringá, Maringá, Paraná, Brazil
| | - Jorge Juarez Vieira Teixeira
- Department of Clinical Analysis and Biomedicine - Laboratory of Epidemiology and Evidence-based Health, Universidade Estadual De Maringá, Maringá, Paraná, Brazil
| | - Maria Valdrinez Campana Lonardoni
- Department of Clinical Analysis and Biomedicine- Laboratory of Leishmaniasis, Universidade Estadual De Maringá, Maringá, Paraná, Brazil
| |
Collapse
|
|
13
|
Ejghal R, Charoute H, Talimi H, Rhazlane S, Lemrani M. Meta-analysis of -308G > A polymorphism in TNFα gene and susceptibility to leishmaniasis. Cytokine 2021; 140:155437. [PMID: 33503580 DOI: 10.1016/j.cyto.2021.155437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 12/04/2020] [Accepted: 12/29/2020] [Indexed: 11/18/2022]
Abstract
The clinical spectrum of leishmaniasis depends on several factors, including Leishmania species and immunogenetic factors. Tumor necrosis factor α (TNFα) plays a central role in immunity against intracellular infections. Many studies have reported that TNFα-308G > A polymorphism is associated with susceptibility to intracellular infections and influences TNFα production. Some studies on the implications of TNFα-308G > A polymorphism in the susceptibility to cutaneous leishmaniasis and visceral leishmaniasis showed controversial results. To draw an overall conclusion using accurate data analysis by increasing the number of cases studied, a meta-analysis was performed based on data from the studies included in the analysis. A total of 1264 patients and 2350 controls were enrolled in the meta-analysis. The results showed no significant association between allele G and allele A of -308G > A polymorphism and leishmaniasis by taking the two subgroups separately [ORCL = 0.99 (0.84-1.18) and ORVL = 1.19 (0.88-1.59)] or together [OR = 1.04 (0.90-1.20)]. This meta-analysis insinuates the absence of statistical evidence for an association between allele G and allele A of TNFα-308G > A polymorphism and Leishmania infection outcome. This suggests that TNFα, despite its crucial role in the immune response against Leishmania infection, is not the sole determinant factor. Other factors, such as gene-gene and gene-environment interactions, receptors, and signaling pathway efficiency, may influence TNFα function.
Collapse
Affiliation(s)
- Rajaâ Ejghal
- Laboratory of Parasitology and Vector-Borne-diseases, Institut Pasteur du Maroc, Casablanca, Morocco.
| | - Hicham Charoute
- Bio-Informatics Department, Institut Pasteur du Maroc, Morocco
| | - Hasnaa Talimi
- Laboratory of Parasitology and Vector-Borne-diseases, Institut Pasteur du Maroc, Casablanca, Morocco; National School of Applied Sciences, Tangier, Morocco
| | - Sara Rhazlane
- National School of Applied Sciences, Tangier, Morocco
| | - Meryem Lemrani
- Laboratory of Parasitology and Vector-Borne-diseases, Institut Pasteur du Maroc, Casablanca, Morocco
| |
Collapse
|
|
14
|
Malta-Santos H, Fukutani KF, Sorgi CA, Queiroz ATL, Nardini V, Silva J, Lago A, Carvalho LP, Machado PLR, Bozza PT, França-Costa J, Faccioli LH, Carvalho EM, Andrade BB, Borges VM. Multi-omic Analyses of Plasma Cytokines, Lipidomics, and Transcriptomics Distinguish Treatment Outcomes in Cutaneous Leishmaniasis. iScience 2020; 23:101840. [PMID: 33313489 PMCID: PMC7721649 DOI: 10.1016/j.isci.2020.101840] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/09/2020] [Accepted: 11/18/2020] [Indexed: 12/13/2022] Open
Abstract
Leishmania braziliensis infection frequently results in cutaneous leishmaniasis (CL). An increase in incidence of drug-resistant CL leading to treatment failure has been reported. Identification of reliable predictors of treatment outcomes is necessary to optimize patient care. Here, we performed a prospective case-control study in which plasma levels of cytokines and lipid mediators were assessed at different time points during antileishmanial therapy in patients with CL from Brazil. Multidimensional analyses were employed to describe a combination of biomarkers able to predict and characterize treatment failure. We found a biosignature influenced mainly by plasma levels of lipid mediators that accurately predicted treatment failure. Furthermore, transcriptomic analysis of a publicly available data set revealed that expression levels of genes related to lipid metabolism measured in skin lesions could distinguish treatment outcomes in CL. Thus, activation of pathways linked to lipid biosynthesis predicts treatment failure in CL. The biomarkers identified may be further explored as therapeutic targets.
Collapse
Affiliation(s)
- Hayna Malta-Santos
- Faculdade de Medicina da Bahia (FAMED), Universidade Federal da Bahia, Salvador, Brazil.,Instituto Gonçalo Moniz (IGM), Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil
| | - Kiyoshi F Fukutani
- Instituto Gonçalo Moniz (IGM), Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil.,Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER), Salvador, Brazil
| | - Carlos A Sorgi
- Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP-USP), Universidade de São Paulo (USP), São Paulo, Brazil
| | - Artur T L Queiroz
- Instituto Gonçalo Moniz (IGM), Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil.,Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER), Salvador, Brazil
| | - Viviane Nardini
- Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP-USP), Universidade de São Paulo (USP), São Paulo, Brazil
| | - Juliana Silva
- Serviço de Imunologia, C-HUPES, Universidade Federal da Bahia, Salvador, Brazil
| | - Alex Lago
- Serviço de Imunologia, C-HUPES, Universidade Federal da Bahia, Salvador, Brazil
| | - Lucas P Carvalho
- Instituto Gonçalo Moniz (IGM), Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil.,Serviço de Imunologia, C-HUPES, Universidade Federal da Bahia, Salvador, Brazil
| | - Paulo L R Machado
- Serviço de Imunologia, C-HUPES, Universidade Federal da Bahia, Salvador, Brazil
| | - Patrícia T Bozza
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Jaqueline França-Costa
- Instituto Gonçalo Moniz (IGM), Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil.,Serviço de Imunologia, C-HUPES, Universidade Federal da Bahia, Salvador, Brazil
| | - Lucia H Faccioli
- Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP-USP), Universidade de São Paulo (USP), São Paulo, Brazil
| | - Edgar M Carvalho
- Faculdade de Medicina da Bahia (FAMED), Universidade Federal da Bahia, Salvador, Brazil.,Instituto Gonçalo Moniz (IGM), Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil.,Serviço de Imunologia, C-HUPES, Universidade Federal da Bahia, Salvador, Brazil
| | - Bruno B Andrade
- Faculdade de Medicina da Bahia (FAMED), Universidade Federal da Bahia, Salvador, Brazil.,Instituto Gonçalo Moniz (IGM), Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil.,Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER), Salvador, Brazil.,Escola Bahiana de Medicina e Saúde Pública, Salvador, Brazil.,Universidade Salvador (UNIFACS), Laureate Universities, Salvador, Brazil
| | - Valéria M Borges
- Faculdade de Medicina da Bahia (FAMED), Universidade Federal da Bahia, Salvador, Brazil.,Instituto Gonçalo Moniz (IGM), Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil
| |
Collapse
|
|
15
|
González-Tafoya E, Diupotex M, Zamora-Chimal J, Salaiza-Suazo N, Ruiz-Remigio A, Becker I. TNF contributes to T-cell exhaustion in chronic L. mexicana infections of mice through PD-L1 up-regulation. Cell Immunol 2020; 358:104196. [PMID: 33032241 DOI: 10.1016/j.cellimm.2020.104196] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 07/14/2020] [Accepted: 07/15/2020] [Indexed: 12/31/2022]
Abstract
Leishmania mexicana can produce chronic infections leading to exhausted T cell phenotypes, mediated by PD-1/PD-L1. Little is known on mechanisms that induce these inhibitory molecules in chronic leishmaniasis. We analyzed factors that contribute to exhausted phenotypes in chronic L. mexicana infections of mice. Our results show that draining lymph node cells express enhanced levels of PD-1/PD-L1. T lymphocytes producing low cytokine levels were also found. L. mexicana infection of dendritic cells (DCs) produced elevated amounts of TNF and showed up-regulation of PD-L1 expression. We provide evidence that T cells of chronic L. mexicana infections in mice are functionally exhausted due to chronic TNF production, which leads to PD-L1 up-regulation in DCs. We conclude that TNF has a fundamental role in promoting T cell exhaustion during chronic L. mexicana infections, which contributes to the inability of T cells to proliferate and produce pro-inflammatory cytokines, thus favoring disease progression.
Collapse
Affiliation(s)
- Eddie González-Tafoya
- Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Hospital General de México, Dr. Balmis 148, Ciudad de México C. P. 06726, Mexico
| | - Mariana Diupotex
- Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Hospital General de México, Dr. Balmis 148, Ciudad de México C. P. 06726, Mexico
| | - Jaime Zamora-Chimal
- Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Hospital General de México, Dr. Balmis 148, Ciudad de México C. P. 06726, Mexico
| | - Norma Salaiza-Suazo
- Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Hospital General de México, Dr. Balmis 148, Ciudad de México C. P. 06726, Mexico
| | - Adriana Ruiz-Remigio
- Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Hospital General de México, Dr. Balmis 148, Ciudad de México C. P. 06726, Mexico
| | - Ingeborg Becker
- Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Hospital General de México, Dr. Balmis 148, Ciudad de México C. P. 06726, Mexico.
| |
Collapse
|
|
16
|
Aznag FZ, Elouilamine E, Korrida A, Izaabel EH. Polymorphisms in the Tumor Necrosis Factor Genes Are Associated with Breast Cancer in the Moroccan Population. Genet Test Mol Biomarkers 2020; 24:592-599. [PMID: 32735459 DOI: 10.1089/gtmb.2020.0073] [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] [Indexed: 12/09/2022] Open
Abstract
Background: The multifunctional cytokines of the tumor necrosis factor (TNF) family have been found to be involved in the promotion of inflammatory responses, and to play critical roles in the pathogenesis of inflammatory, autoimmune, and malignant diseases. The aim of the present study was to assess the associations among the TNFα -238 G > A (rs361525), TNFα -308 G > A (rs1800629), and TNFβ +252 A>G (rs909253) polymorphisms, and the breast cancer (BC) susceptibility in the Moroccan population. Materials and Methods: We conducted a case-control study, including 492 participants made up of 264 pathologically confirmed BC subjects, and 228 healthy women as controls. The samples were genotyped by means of polymerase chain reaction-restriction fragment length polymorphism analyses. Results: The TNFα -238 G > A and TNFα -308 G > A polymorphisms were significantly associated with increased risk of BC for the AA genotype, while, the AG genotype of TNFβ +252 A>G may offer a protective effect in this population. Haplotypic analyses showed that the GAA and AAG haplotypes increased the risk significantly for BC. Moreover, a significant association was observed between polymorphisms at the TNFα -238 A>G locus and the clinical profiles of the patients with regard to their estrogen-and progesterone-positive receptor status. Conclusion: These findings indicate that TNF gene polymorphisms are linked with the risk of BC in the Moroccan population. Further studies implementing a larger sample size are needed to support our findings.
Collapse
Affiliation(s)
- Fatima Zahra Aznag
- Laboratory of Cellular Biology and Molecular Genetics, Faculty of Sciences, Ibn Zohr University, Agadir, Morocco
| | - Ezohra Elouilamine
- Laboratory of Cellular Biology and Molecular Genetics, Faculty of Sciences, Ibn Zohr University, Agadir, Morocco
| | - Amal Korrida
- Laboratory of Cellular Biology and Molecular Genetics, Faculty of Sciences, Ibn Zohr University, Agadir, Morocco.,Higher Institute of Nursing Professions and Health Techniques of Agadir, Ministry of Health, Agadir, Morocco
| | - El Hassan Izaabel
- Laboratory of Cellular Biology and Molecular Genetics, Faculty of Sciences, Ibn Zohr University, Agadir, Morocco
| |
Collapse
|
|
17
|
Kirik FE, Ülger M, Tezcan Ülger S, Aslan G. Association of cytokine gene polymorphisms with susceptibility to cutaneous leishmaniasis in a Turkish population. Parasite Immunol 2020; 42:e12775. [PMID: 32656817 DOI: 10.1111/pim.12775] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 07/08/2020] [Indexed: 01/29/2023]
Abstract
AIMS The objective of this study was to determine the association of TNF-α -308 G/A, IFN-γ +874 T/A, IL-12B + 1188 A/C, IL-10 -1082 G/A and IL-4 -590 C/T polymorphisms with susceptibility to CL. METHODS AND RESULTS A total of 55 CL patients and 110 controls from Sanlıurfa province of Turkey were included to this study. Polymorphisms were genotyped by 'polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)' and 'amplification refractory mutation system-PCR (ARMS-PCR)' methods. A statistically significant difference was noted in the allele (P < .001, P = .002) and genotype (P < .001, P = .001,) frequencies of TNF-α -308 G/A and IL-4 -590 C/T, respectively. TNF-α 308 GG versus GA genotype (OR = 19.556 [95% CI 8.310-46.019] P < .001), GG versus GA + AA genotype (OR = 20.444 [95% CI 8.707-48.004] P < .001) and G versus A allele (OR = 6.968 [95% CI 3.903-12.440] P < .001) revealed significant association with CL. IL-4 -590 CC versus TT + CT genotype (OR = 2.049 [95% CI 1.025-4.096], P = .041) and C versus T allele (OR = 2.441 [95% CI 1.355-4.396], P = .002) revealed significant association with CL. CONCLUSION Our study indicates that TNF-α 308 G/A and IL-4-590 C/T polymorphisms are significantly associated with susceptibility to CL. Individuals carrying A allele at TNF-α promoter -308 position and T allele at IL-4 promoter -590 position are at a higher risk for CL.
Collapse
Affiliation(s)
- Fatma Esin Kirik
- Department of Medical Microbiology, Faculty of Medicine, Nigde Ömer Halisdemir University, Niğde, Turkey
| | - Mahmut Ülger
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Mersin University, Mersin, Turkey
| | - Seda Tezcan Ülger
- Department of Medical Microbiology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Gönül Aslan
- Department of Medical Microbiology, Faculty of Medicine, Mersin University, Mersin, Turkey
| |
Collapse
|
|
18
|
Blackwell JM, Fakiola M, Castellucci LC. Human genetics of leishmania infections. Hum Genet 2020; 139:813-819. [PMID: 32055998 PMCID: PMC7272388 DOI: 10.1007/s00439-020-02130-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 02/02/2020] [Indexed: 01/15/2023]
Abstract
Identifying genetic risk factors for parasitic infections such as the leishmaniases could provide important leads for improved therapies and vaccines. Until recently most genetic studies of human leishmaniasis were underpowered and/or not replicated. Here, we focus on recent genome-wide association studies of visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL). For VL, analysis across 2287 cases and 2692 controls from three cohorts identified a single major peak of genome-wide significance (Pcombined = 2.76 × 10-17) at HLA-DRB1-HLA-DQA1. HLA-DRB1*1501 and DRB1*1404/DRB1*1301 were the most significant protective versus risk alleles, respectively, with specific residues at amino acid positions 11 and 13 unique to protective alleles. Epitope-binding studies showed higher frequency of basic AAs in DRB1*1404-/*1301-specific epitopes compared to hydrophobic and polar AAs in DRB1*1501-specific epitopes at anchor residues P4 and P6 which interact with residues at DRB1 positions 11 and 13. For CL, genome-wide significance was not achieved in combined analysis of 2066 cases and 2046 controls across 2 cohorts. Rather, multiple top hits at P < 5 × 10-5 were observed, amongst which IFNG-AS1 was of specific interest as a non-coding anti-sense RNA known to influence responses to pathogens by increasing IFN-γ secretion. Association at LAMP3 encoding dendritic cell lysosomal associated membrane protein 3 was also interesting. LAMP3 increases markedly upon activation of dendritic cells, localizing to the MHC Class II compartment immediately prior to translocation of Class II to the cell surface. Together these GWAS results provide firm confirmation for the importance of antigen presentation and the regulation of IFNγ in determining the outcome of Leishmania infections.
Collapse
Affiliation(s)
- Jenefer M Blackwell
- Telethon Kids Institute, The University of Western Australia, Nedlands, WA, Australia.
- Department of Pathology, University of Cambridge, Cambridge, UK.
| | - Michaela Fakiola
- INGM-National Institute of Molecular Genetics "Romeo Ed Enrica Invernizzi" Milan, Milan, Italy
| | - Léa C Castellucci
- National Institute of Science and Technology in Tropical Diseases, Salvador, Brazil
- Federal University of Bahia, Salvador, Brazil
| |
Collapse
|
|
19
|
Ahmed AA, Rasheed Z, Salem T, Al-Dhubaibi MS, Al Robaee AA, Alzolibani AA. TNF-α - 308 G/A and IFN-γ + 874 A/T gene polymorphisms in Saudi patients with cutaneous leishmaniasis. BMC MEDICAL GENETICS 2020; 21:104. [PMID: 32404058 PMCID: PMC7218653 DOI: 10.1186/s12881-020-01043-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 05/05/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND Cutaneous leishmaniasis (CL) is well linked with immunogenetic factors. This study was undertaken to test the association of TNF-α - 308 and IFN-γ + 874 gene polymorphisms with the susceptibility of Leishmania (L) species among CL patients in central region of Saudi Arabia. METHODS This is a case-control study involved 169 Saudi subjects with different L. species and 199 healthy controls from central region of Saudi Arabia. All subjects were characterized by TNF-α - 308 G/A and IFN-γ + 874 A/T gene polymorphisms using PCR. RESULTS Evaluation of genotyping and allelic frequency of TNF-α - 308 G/A in different L. species showed no significant association compared to controls (p > 0.05). Except, in cases of L. tropica that showed significantly higher TNF-α - 308 A versus G allele frequency (p = 0.0004). Evaluation of genotyping of IFN-γ + 874 (TT versus AA+AT recessive) and allelic frequency of IFN-γ + 874 (T versus A) showed significant higher in L. major and also in total CL cases as compared to healthy controls (p < 0.05). Furthermore, a strong association was observed between the susceptibility of L. major, L. tropica or total CL cases with synergistically combined high TNF-α 308/INF-γ 874 alleles. CONCLUSIONS This is the first report that shows the gene polymorphisms of TNF-α - 308 G/A and IFN-γ + 874 A/T in Saudi patients with different L. species infections. Data showed that the TNF-α-308 G/A gene polymorphism is not associated with the susceptibility of CL in Saudi subjects. The only correlation was found in between A versus G allelic frequency in L. tropica. Importantly, IFN-γ + 874 A/T polymorphism was found to be associated with the susceptibility of L. major and also with total CL subjects. Moreover, data from synergistically combined high TNF-α 308/INF-γ 874 alleles strongly suggest their potential role in the susceptibility of leishmania infection.
Collapse
Affiliation(s)
- Ahmed A Ahmed
- Research Center, College of Medicine, Qassim University, Buraidah, Saudi Arabia
| | - Zafar Rasheed
- Department of Medical Biochemistry, College of Medicine, Qassim University, P.O. Box 6655, Buraidah, KSA, 51452, Saudi Arabia.
| | - Tarek Salem
- Department of Medical Biochemistry, College of Medicine, Qassim University, P.O. Box 6655, Buraidah, KSA, 51452, Saudi Arabia
| | - Mohammed S Al-Dhubaibi
- Department of Dermatology, College of Medicine, Qassim University, Buraidah, Saudi Arabia
| | - Ahmad A Al Robaee
- Department of Dermatology, College of Medicine, Qassim University, Buraidah, Saudi Arabia
| | | |
Collapse
|
|
20
|
Effects of Meglumine Antimoniate Treatment on Cytokine Production in a Patient with Mucosal Leishmaniasis and Chagas Diseases Co-Infection. Trop Med Infect Dis 2020; 5:tropicalmed5020069. [PMID: 32370270 PMCID: PMC7345053 DOI: 10.3390/tropicalmed5020069] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 04/09/2020] [Accepted: 04/14/2020] [Indexed: 11/24/2022] Open
Abstract
The influence of antimoniate treatment on specific anti-protozoan T-cell responses was evaluated in a 48-year-old male patient diagnosed with mucosal leishmaniasis and Chagas disease infection. Before and after treatment, PBMC (peripheral blood mononuclear cells) were cultured in the absence or presence of Leishmania braziliensis or Trypanosoma cruzi live parasites, their soluble antigens, or PHA (phytohaemagglutinin). Cytokines were measured and Treg (T regulatory) cell percentages were quantified. Before treatment, PBMC were able to produce higher amounts of TNF-α, IL-6 (Interleukin-6), and IL-10 (Interleukin-10) but lower amounts of IL-12 (Interleukin-12) in response to culture stimulation. However, after treatment, there was a down-modulation of TNF-α, IL-6, and IL-10 cytokines but an up-modulation in IL-12 production. PBMC had the ability to produce TNF-α only against live parasites or PHA. There was an overall decrease of circulating Treg cells after treatment. In mixed Leishmaniasis and Chagas disease infection, treatment with antimoniate could modulate immune responses toward a more protective profile to both diseases.
Collapse
|
|
21
|
Ngere I, Gufu Boru W, Isack A, Muiruri J, Obonyo M, Matendechero S, Gura Z. Burden and risk factors of cutaneous leishmaniasis in a peri-urban settlement in Kenya, 2016. PLoS One 2020; 15:e0227697. [PMID: 31971945 PMCID: PMC6977748 DOI: 10.1371/journal.pone.0227697] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 12/25/2019] [Indexed: 11/24/2022] Open
Abstract
Background Cutaneous leishmaniasis is a neglected disease known to cause significant morbidity among the poor. We investigated a suspected outbreak to determine the magnitude of cases, characterize the cases and identify risk factors of cutaneous leishmaniasis in Gilgil, a peri-urban settlement in Central Kenya. Methods Hospital records for the period 2010–2016 were reviewed and additional cases were identified through active case search. Clinical diagnosis of cutaneous leishmaniasis was made based on presence of ulcerative, nodular or papular skin lesion. The study enrolled 58 cases matched by age and neighbourhood to 116 controls in a case control study. Data was collected using structured questionnaires and simple proportions, means and medians were computed, and logistic regression models were constructed for analysis of individual, indoor and outdoor risk factors. Results Of the 255 suspected cases of cutaneous leishmaniasis identified, females constituted 56% (142/255) and the median age was 7 years (IQR 7–21). Cases occurred in clusters and up to 43% of cases originated from Gitare (73/255) and Kambi-Turkana (36/255) villages. A continuous transmission pattern was depicted throughout the period under review. Individual risk factors included staying outside the residence in the evening after sunset (OR 4.1, CI 1.2–16.2) and visiting forests (OR 4.56, CI 2.04–10.22). Sharing residence with a case (OR 14.4, CI 3.8–79.3), residing in a thatched house (OR 7.9, CI 1.9–45.7) and cracked walls (OR 2.3, CI 1.0–4.9) were identified among indoor factors while sighting rock hyraxes near residence (OR 5.3, CI 2.2–12.7), residing near a forest (OR 7.8, CI 2.8–26.4) and having a close neighbour with cutaneous leishmaniasis (OR 6.8, CI 2.8–16.0) were identified among outdoor factors. Conclusions We identify a large burden of cutaneous leishmaniasis in Gilgil with evidence of individual, indoor and outdoor factors of disease spread. The role of environmental factors and rodents in disease transmission should be investigated further
Collapse
Affiliation(s)
- Isaac Ngere
- Global Health Program-Kenya, Washington State University, Nairobi, Kenya
- Field Epidemiology and Laboratory Training Program, Nairobi, Kenya
- * E-mail:
| | - Waqo Gufu Boru
- Field Epidemiology and Laboratory Training Program, Nairobi, Kenya
- Ministry of Health, Nairobi, Republic of Kenya
| | - Abdikadir Isack
- Field Epidemiology and Laboratory Training Program, Nairobi, Kenya
- Ministry of Health, Nairobi, Republic of Kenya
| | - Joshua Muiruri
- Field Epidemiology and Laboratory Training Program, Nairobi, Kenya
- Ministry of Health, Nairobi, Republic of Kenya
| | - Mark Obonyo
- Field Epidemiology and Laboratory Training Program, Nairobi, Kenya
- Ministry of Health, Nairobi, Republic of Kenya
| | | | - Zeinab Gura
- Field Epidemiology and Laboratory Training Program, Nairobi, Kenya
- Ministry of Health, Nairobi, Republic of Kenya
| |
Collapse
|
|
22
|
Aznag FZ, Moutaoufik MT, Korrida A, Izaabel EH. Genetic Distribution of the LTA +252 A>G and TNFA -308 G > A Polymorphisms in the Moroccan Population. Genet Test Mol Biomarkers 2019; 23:871-876. [PMID: 31738572 DOI: 10.1089/gtmb.2019.0116] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Introduction: The LTA and TNFA genes encode key proinflammatory cytokines with diverse activities in the immune responses. Single nucleotide polymorphisms (SNPs) in the LTA rs909253 (+252 A > G) and TNFA rs1800629 (-308 G > A) genes have been associated with susceptibility to many complex diseases. The aim of this study was to assess the frequency for these two key polymorphisms in the Moroccan population. Materials and Methods: A total of 338 unrelated healthy Moroccan subjects were genotyped for the two alleles using a restriction fragment length polymorphism-polymerase chain reaction method. Results: The LTA (+252 A > G) and TNFA (-308 G > A) were the most common alleles with 67.9% and 74.8% frequencies, respectively. In addition to the linkage disequilibrium between the two SNPs, significant differences in allele frequencies were observed in Moroccan population compared with Mediterraneans, Europeans, Africans, South Americans, and Asians (p < 0.05). Finally, genetic proximities between Moroccan, European, and West African populations were found by means of the principal component analysis. Conclusion: The LTA +252 A>G and TNFA -308 G > A polymorphisms among Moroccan population follow the patterns commonly encountered in other Mediterranean, European, and African populations. The result of this study could contribute in developing a genetic database on the healthy Moroccan population.
Collapse
Affiliation(s)
- Fatima Zahra Aznag
- Laboratory of Cellular Biology and Molecular Genetics, Faculty of Sciences, Ibn Zohr University, Agadir, Morocco
| | | | - Amal Korrida
- Laboratory of Cellular Biology and Molecular Genetics, Faculty of Sciences, Ibn Zohr University, Agadir, Morocco.,Higher Institute of Nursing Professions and Health Techniques of Agadir, Ministry of Health, Agadir, Morocco
| | - El Hassan Izaabel
- Laboratory of Cellular Biology and Molecular Genetics, Faculty of Sciences, Ibn Zohr University, Agadir, Morocco
| |
Collapse
|
|
23
|
Tumour necrosis factor gene polymorphisms in Egyptian patients with rheumatoid arthritis and their relation to disease activity and severity. Cent Eur J Immunol 2019; 44:277-284. [PMID: 31933537 PMCID: PMC6953370 DOI: 10.5114/ceji.2019.89602] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2016] [Accepted: 01/24/2017] [Indexed: 11/17/2022] Open
Abstract
Aim of the study The present case control study was conducted to assess the association of LTA 252 A>G, TNF-α 308 G>A, and TNF-α 1031 T>C gene polymorphisms with rheumatoid arthritis (RA), and their involvement in disease activity and severity. Material and methods A total of 70 Egyptians, including 35 RA patients and 35 healthy control individuals, were included in the study. The RA patients comprised 34 females and one male. Cases with RA were diagnosed by a rheumatologist and fulfilled the 2010 ACR/EULAR criteria. Modified disease activity score (DAS28) was used to assess disease activity. Van Der Heijde-modified Sharp score (vdHSS) was used to assess radiological changes for assessment of disease severity. PCR-RFLP was used to detect the association of LTA 252 A>G, TNF-α 308 G>A, and TNF-α 1031 T>C gene polymorphisms with RA. Results TNF-α 308 G allele and TNF-α 308 GG genotype were significantly higher in RA patients compared to healthy control subjects (p = 0.04 and p = 0.001, respectively). TNF-α 308 G allele and GG genotype were significantly higher in the RA non-remission group compared to the remission group (p = 0.008, p < 0.001). Patients with the TNF-α 308 AG genotype had higher mean of Sharp score compared to the patients with the GG and AA genotypes (p = 0.007). There was no significant association between LTA 252 A>G and TNF-α 1031 T>C gene polymorphisms and RA. Conclusions Our results suggest that TNF-α 308 G/A gene polymorphism is genetically associated with RA and involved in disease activity and severity in Egyptian patients.
Collapse
|
|
24
|
Gonçalves de Albuquerque SDC, da Costa Oliveira CN, Vaitkevicius-Antão V, Silva AC, Luna CF, de Lorena VMB, de Paiva-Cavalcanti M. Study of association of the rs2275913 IL-17A single nucleotide polymorphism and susceptibility to cutaneous leishmaniasis caused by Leishmania braziliensis. Cytokine 2019; 123:154784. [PMID: 31344596 DOI: 10.1016/j.cyto.2019.154784] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Revised: 05/23/2019] [Accepted: 07/16/2019] [Indexed: 12/14/2022]
Abstract
Cutaneous leishmaniasis (CL) caused by Leishmania braziliensis is the most spread clinical form of leishmaniasis in Brazil. However, only a few part of the people infected develop clinically perceptive disease, suggesting the influence of human genetic components in the CL pathogeny. The rs2275913 SNP is the nucleotide variant of the IL17A gene. The A allele is associated with a vast number of infectious and non-infectious diseases. Here, we investigated the association of the rs2275913 SNP (G/A) from IL-17A and two forms of susceptibility to CL in Brazil by case-control study. Furthermore, we evaluated the functional relevance of this SNP during the immune response of the host and analyzed its impact in the parasite elimination. Weak associations of A allele with susceptibility to L. braziliensis infection or to symptomatic CL were observed, and a tendency of A allele carriers to be more susceptible to infection and cutaneous disease. Functional analysis of the Th17 cell phenotypes revealed lower frequencies of CD4+ IL-17+ cells in samples of infected people with AA/AG genotypes. Furthermore, people carrying the A allele maintain higher parasite loads, reinforcing the genetic susceptibility findings. This study adds knowledge about the influence of a significant genetic variation on IL-17 promoter on CL pathogenesis, and may contribute to enhance the knowledge about the role of IL-17 in the L. braziliensis infections.
Collapse
Affiliation(s)
- Suênia da Cunha Gonçalves de Albuquerque
- Department of Microbiology, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Av. Prof. Moraes Rego S/N, 50670-420 Recife, Pernambuco, Brazil; Central Laboratory of Public Health Dr Milton Bezerra de Sobral, Rua João Fernandes Vieira S/N, 50050-215 Recife, Pernambuco, Brazil
| | - Cíntia Nascimento da Costa Oliveira
- Department of Microbiology, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Av. Prof. Moraes Rego S/N, 50670-420 Recife, Pernambuco, Brazil
| | - Victor Vaitkevicius-Antão
- Department of Microbiology, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Av. Prof. Moraes Rego S/N, 50670-420 Recife, Pernambuco, Brazil
| | - Ana Carla Silva
- Department of Microbiology, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Av. Prof. Moraes Rego S/N, 50670-420 Recife, Pernambuco, Brazil
| | - Carlos Feitosa Luna
- Department of Microbiology, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Av. Prof. Moraes Rego S/N, 50670-420 Recife, Pernambuco, Brazil
| | - Virgínia Maria Barros de Lorena
- Department of Immunology, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Av. Prof. Moraes Rego S/N, 50670-420 Recife, Pernambuco, Brazil
| | - Milena de Paiva-Cavalcanti
- Department of Microbiology, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Av. Prof. Moraes Rego S/N, 50670-420 Recife, Pernambuco, Brazil.
| |
Collapse
|
|
25
|
Shehadeh FVB, Santos RRD, Silva LADD, Silva Júnior WVD, Ribas-Silva R, Ribas AD, Silveira TGV, Borelli SD, Aristides SMA. TGF-β1 polymorphism in American tegumentary leishmaniasis in a Southern Brazilian population. Rev Soc Bras Med Trop 2019; 52:e20170415. [DOI: 10.1590/0037-8682-0415-2017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Accepted: 08/14/2018] [Indexed: 11/21/2022] Open
|
|
26
|
Ávila LR, Gomes CM, Oliveira PG, Gomes RS, Vinaud MC, Dorta ML, Uliana SRB, Ribeiro-Dias F, Oliveira MAP. Promastigote parasites cultured from the lesions of patients with mucosal leishmaniasis are more resistant to oxidative stress than promastigotes from a cutaneous lesion. Free Radic Biol Med 2018; 129:35-45. [PMID: 30196081 DOI: 10.1016/j.freeradbiomed.2018.09.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 09/03/2018] [Accepted: 09/05/2018] [Indexed: 01/03/2023]
Abstract
Human leishmaniasis caused by Leishmania (Viannia) braziliensis can be presented as localized cutaneous leishmaniasis (LCL) or mucosal leishmaniasis (ML). Macrophages kill parasites using nitric oxide (NO) and reactive oxygen species (ROS). The aim of this study was to evaluate the ability of parasites obtained from patients with LCL or ML to produce and resist NO or ROS. Promastigotes and amastigotes from LCL or ML isolates produced similar amounts of NO in culture. Promastigotes from ML isolates were more resistant to NO and H2O2 than LCL parasites in a stationary phase, whereas amastigotes from LCL isolates were more resistant to NO. In addition, in the stationary phase, promastigote isolates from patients with ML expressed more thiol-specific antioxidant protein (TSA) than LCL isolates. Therefore it is suggested that infective promastigotes from ML isolates are more resistant to microbicidal mechanisms in the initial phase of infection. Subsequently, amastigotes lose this resistance. This behavior of ML parasites can decrease the number of parasites capable of stimulating the host immune response shortly after the infection establishment.
Collapse
MESH Headings
- Animals
- Antioxidants/chemistry
- Antioxidants/metabolism
- Antiprotozoal Agents/pharmacology
- Culture Media/chemistry
- Female
- Host-Parasite Interactions
- Humans
- Hydrogen Peroxide/pharmacology
- Immunity, Innate
- Leishmania braziliensis/drug effects
- Leishmania braziliensis/growth & development
- Leishmania braziliensis/isolation & purification
- Leishmania braziliensis/metabolism
- Leishmaniasis, Diffuse Cutaneous/immunology
- Leishmaniasis, Diffuse Cutaneous/metabolism
- Leishmaniasis, Diffuse Cutaneous/parasitology
- Leishmaniasis, Mucocutaneous/immunology
- Leishmaniasis, Mucocutaneous/metabolism
- Leishmaniasis, Mucocutaneous/parasitology
- Life Cycle Stages/drug effects
- Life Cycle Stages/physiology
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Knockout
- Nitric Oxide/metabolism
- Nitric Oxide/pharmacology
- Nitric Oxide Donors/pharmacology
- Nitroprusside/pharmacology
- Protozoan Proteins/genetics
- Protozoan Proteins/metabolism
Collapse
Affiliation(s)
- Lucilla Ribeiro Ávila
- Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Rua 235 S/N, Goiânia, Goiás 74605-050, Brazil
| | - Clayson Moura Gomes
- Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Rua 235 S/N, Goiânia, Goiás 74605-050, Brazil; Pontifícia Universidade Católica de Goiás, Av, Universitária 1069, Setor Universitário, Goiânia, Goiás 74605-010, Brazil
| | - Pollyana Guimarães Oliveira
- Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Rua 235 S/N, Goiânia, Goiás 74605-050, Brazil
| | - Rodrigo Saar Gomes
- Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Rua 235 S/N, Goiânia, Goiás 74605-050, Brazil
| | - Marina Clare Vinaud
- Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Rua 235 S/N, Goiânia, Goiás 74605-050, Brazil
| | - Miriam Leandro Dorta
- Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Rua 235 S/N, Goiânia, Goiás 74605-050, Brazil
| | - Silvia Reni Bortolin Uliana
- Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Prof. Lineu Prestes 1374, São Paulo, SP 05508-000, Brazil
| | - Fátima Ribeiro-Dias
- Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Rua 235 S/N, Goiânia, Goiás 74605-050, Brazil
| | - Milton Adriano Pelli Oliveira
- Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Rua 235 S/N, Goiânia, Goiás 74605-050, Brazil.
| |
Collapse
|
|
27
|
Yen TY, Shih WL, Huang YC, Lee JT, Huang LM, Chang LY. Polymorphisms in enterovirus 71 receptors associated with susceptibility and clinical severity. PLoS One 2018; 13:e0206769. [PMID: 30395634 PMCID: PMC6218064 DOI: 10.1371/journal.pone.0206769] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 10/18/2018] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVE To evaluate the association of enterovirus 71 (EV71) susceptibility and clinical severity with polymorphisms in EV71 receptors, including human scavenger receptor class B member 2 (SCARB2), P-selectin glycoprotein ligand-1 (PSGL-1), and annexin II (ANXA2). METHODS We enrolled laboratory-confirmed EV71 cases and healthy age- and gender-matched controls in Taiwan from 2000 to 2012. We detected genetic polymorphisms in SCARB2, PSGL-1, and ANXA2 and correlated the results with EV71 susceptibility and severity. RESULTS We collected 599 EV71 cases and 98 controls. Among EV71 patients, the male to female ratio was 1.61, and the mean age was 2.99±2.47 years. For clinical severity, 117 (19.6%) had severe central nervous system involvement with or without cardiopulmonary failure. For outcomes, 46 (7.7%) had sequelae, and 14 (2.3%) died. SCARB2 polymorphisms (rs6824953 and rs11097262) were associated with susceptibility to EV71 infection (OR 1.60, 95% CI 1.07-2.39; and OR 1.64, 95% CI 1.09-2.47, respectively). PSGL-1 polymorphisms (rs7137098 and rs8179137) were significantly associated with severe EV71 infection (OR 1.46, 95% CI 1.1-1.96; and OR 1.47, 95% CI 1.07-2.03, respectively). CONCLUSIONS SCARB2 polymorphisms (rs6824953 and rs11097262) might be associated with EV71 susceptibility. PSGL-1 polymorphisms (rs7137098 and rs8179137) were associated with severe EV71 infection.
Collapse
Affiliation(s)
- Ting-Yu Yen
- Department of Pediatrics, China Medical University Children’s Hospital, China Medical University, Taichung, Taiwan
| | - Wei-Liang Shih
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Yi-Chuan Huang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jian-Te Lee
- Department of Pediatrics, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan
| | - Li-Min Huang
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Luan-Yin Chang
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| |
Collapse
|
|
28
|
Sousa R, Andrade VM, Bair T, Ettinger NA, Guimarães L, Andrade L, Guimarães LH, Machado PRL, Carvalho EM, Wilson ME, Schriefer A. Early Suppression of Macrophage Gene Expression by Leishmania braziliensis. Front Microbiol 2018; 9:2464. [PMID: 30374342 PMCID: PMC6196312 DOI: 10.3389/fmicb.2018.02464] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 09/26/2018] [Indexed: 01/27/2023] Open
Abstract
Leishmania braziliensis is an intracellular parasite that resides mostly in macrophages. Both the parasite genome and the clinical disease manifestations show considerable polymorphism. Clinical syndromes caused by L. braziliensis include localized cutaneous (CL), mucosal (ML), and disseminated leishmaniasis (DL). Our prior studies showed that genetically distinct L. braziliensis clades associate with different clinical types. Herein, we hypothesized that: (1) L. braziliensis induces changes in macrophage gene expression that facilitates infection; (2) infection of macrophages with strains associated with CL (clade B), ML (clade C), or DL (clade A) will differentially affect host cell gene expression, reflecting their different pathogenic mechanisms; and (3) differences between the strains will be reflected by differences in macrophage gene expression after initial exposure to the parasite. Human monocyte derived macrophages were infected with L. braziliensis isolates from clades A, B, or C. Patterns of gene expression were compared using Affymetrix DNA microarrays. Many transcripts were significantly decreased by infection with all isolates. The most dramatically decreased transcripts encoded proteins involved in signaling pathways, apoptosis, or mitochondrial oxidative phosphorylation. Some transcripts encoding stress response proteins were up-regulated. Differences between L. braziliensis clades were observed in the magnitude of change, rather than the identity of transcripts. Isolates from subjects with metastatic disease (ML and DL) induced a greater magnitude of change than isolates from CL. We conclude that L. braziliensis enhances its intracellular survival by inhibiting macrophage pathways leading to microbicidal activity. Parasite strains destined for dissemination may exert a more profound suppression than less invasive L. braziliensis strains that remain near the cutaneous site of inoculation.
Collapse
Affiliation(s)
- Rosana Sousa
- Serviço de Imunologia, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil
| | - Viviane M Andrade
- Serviço de Imunologia, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil
| | - Thomas Bair
- DNA Facility, The University of Iowa, Iowa City, IA, United States
| | - Nicholas A Ettinger
- Deptartment of Pediatrics-Critical Care, Baylor College of Medicine, Houston, TX, United States
| | - Luana Guimarães
- Serviço de Imunologia, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil
| | - Laura Andrade
- Serviço de Imunologia, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil
| | - Luiz H Guimarães
- Centro de Formação em Saúde, Universidade Federal do Sul da Bahia, Teixeira de Freitas, Brazil.,Instituto Nacional de Ciência e Tecnologia - Doenças Tropicais, Salvador, Brazil
| | - Paulo R L Machado
- Serviço de Imunologia, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil.,Instituto Nacional de Ciência e Tecnologia - Doenças Tropicais, Salvador, Brazil
| | - Edgar M Carvalho
- Serviço de Imunologia, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil.,Instituto Nacional de Ciência e Tecnologia - Doenças Tropicais, Salvador, Brazil.,Instituto Gonçalo Moniz, FIOCRUZ, Salvador, Brazil
| | - Mary E Wilson
- Departments of Internal Medicine and Microbiology, VA Medical Center, The University of Iowa, Iowa City, IA, United States
| | - Albert Schriefer
- Serviço de Imunologia, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil.,Instituto Nacional de Ciência e Tecnologia - Doenças Tropicais, Salvador, Brazil.,Departamento de Ciências da Biointeração, Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador, Brazil
| |
Collapse
|
|
29
|
Silva PCV, Gomes AV, de Britto LRPB, de Lima ELS, da Silva JL, Montenegro SML, Muniz MTC, Domingues ALC. Influence of a TNF-α Polymorphism on the Severity of Schistosomiasis Periportal Fibrosis in the Northeast of Brazil. Genet Test Mol Biomarkers 2017; 21:658-662. [PMID: 29087736 DOI: 10.1089/gtmb.2017.0133] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIMS The proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) is an essential component in the host immune response to infection, and it has been reported to be an important mediator in severe periportal fibrosis (PPF). We hypothesized that the (-G308A) polymorphism of the TNF-α gene is associated with the severity of PPF and that these polymorphisms influence TNF-α expression. METHODS In this cross-sectional study, we genotyped these polymorphisms within the TNF-α gene in 256 Brazilian subjects infected with Schistosoma mansoni, with different patterns of PPF. RESULTS The genotype (-308) AA was associated with a significant increase in the risk to advanced PPF (OR = 4.60; p = 0.009). In addition, median levels of TNF-α were higher in patients with moderate to advanced PPF, compared with mild fibrosis (20 and 17.3 pg/mL, respectively; p = 0.040). There was no association between average serum levels of TNF-α and (-G308A) TNF-α polymorphism. CONCLUSIONS Our results suggest the (-308) AA genotype may be a risk factor for severity in advanced PPF, in this Brazilian population, and could potentially be used to predict the severity of advanced PPF in schistosomiasis.
Collapse
Affiliation(s)
- Paula Carolina Valença Silva
- 1 Departamento de Enfermagem, Universidade Federal de Pernambuco (UFPE) , Vitória de Santo Antão, Pernambuco, Brazil .,2 Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica, Hospital Universitário Oswaldo Cruz , Universidade de Pernambuco, Recife, Pernambuco, Brazil
| | - Adriana Vieira Gomes
- 2 Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica, Hospital Universitário Oswaldo Cruz , Universidade de Pernambuco, Recife, Pernambuco, Brazil .,3 Instituto de Ciências Biológicas, Universidade de Pernambuco (UPE) , Recife, Brazil
| | - Lidiane Régia Pereira Braga de Britto
- 2 Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica, Hospital Universitário Oswaldo Cruz , Universidade de Pernambuco, Recife, Pernambuco, Brazil .,4 Departamento de Fisioterapia, Universidade de Pernambuco (UPE) , Petrolina, Brazil
| | - Elker Lene Santos de Lima
- 2 Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica, Hospital Universitário Oswaldo Cruz , Universidade de Pernambuco, Recife, Pernambuco, Brazil
| | - Jamile Luciana da Silva
- 1 Departamento de Enfermagem, Universidade Federal de Pernambuco (UFPE) , Vitória de Santo Antão, Pernambuco, Brazil
| | | | - Maria Tereza Cartaxo Muniz
- 2 Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica, Hospital Universitário Oswaldo Cruz , Universidade de Pernambuco, Recife, Pernambuco, Brazil .,3 Instituto de Ciências Biológicas, Universidade de Pernambuco (UPE) , Recife, Brazil
| | | |
Collapse
|
|
30
|
de Vasconcelos TCB, Furtado MC, Belo VS, Morgado FN, Figueiredo FB. Canine susceptibility to visceral leishmaniasis: A systematic review upon genetic aspects, considering breed factors and immunological concepts. INFECTION GENETICS AND EVOLUTION 2017; 74:103293. [PMID: 28987807 DOI: 10.1016/j.meegid.2017.10.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 09/30/2017] [Accepted: 10/03/2017] [Indexed: 01/01/2023]
Abstract
Dogs have different susceptibility degrees to leishmaniasis; however, genetic research on this theme is scarce, manly on visceral form. The aims of this systematic review were to describe and discuss the existing scientific findings on genetic susceptibility to canine leishmaniasis, as well as to show the gaps of the existing knowledge. Twelve articles were selected, including breed immunological studies, genome wide associations or other gene polymorphism or gene sequencing studies, and transcription approaches. As main results of literature, there was a suggestion of genetic clinical resistance background for Ibizan Hound dogs, and alleles associated with protection or susceptibility to visceral leishmaniasis in Boxer dogs. Genetic markers can explain phenotypic variance in both pro- and anti-inflammatory cytokines and in cellular immune responses, including antigen presentation. Many gene segments are involved in canine visceral leishmaniasis phenotype, with Natural Resistance Associated Macrophage Protein 1 (NRAMP1) as the most studied. This was related to both protection and susceptibility. In comparison with murine and human genetic approaches, lack of knowledge in dogs is notorious, with many possibilities for new studies, revealing a wide field to be assessed on canine leishmaniasis susceptibility research.
Collapse
Affiliation(s)
- Tassia Cristina Bello de Vasconcelos
- Centro de Controle de Zoonoses, Vigilância em Saúde, Secretaria Municipal de Saúde, Prefeitura Municipal de Resende, Rua Euridices Paulina de Almeida, 300, Vicentina II, Resende, RJ 27500-000, Brazil.
| | - Marina Carvalho Furtado
- Fiocruz Mata Atlântica, Fundação Oswaldo Cruz, Estrada Rodrigues Caldas, 3400, Taquara, Rio de Janeiro, RJ 22713-375, Brazil
| | - Vinícius Silva Belo
- Universidade Federal de São João del-Rei, campus Centro Oeste Dona Lindu, Rua Sebastião Gonçalves Coelho, 400, Chanadour, Divinópolis, MG 35.501-296, Brazil
| | - Fernanda Nazaré Morgado
- Laboratório de Pesquisa em Leishmaniose, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil, 4365, Manguinhos, Rio de Janeiro, RJ 21040-360, Brazil
| | - Fabiano Borges Figueiredo
- Laboratório de Biologia Celular, Instituto Carlos Chagas, Rua Professor Algacyr Munhoz Mader, 3.775, CIC, campus do Tecpar, bloco C, Curitiba, PR 81.350-010 Brazil
| |
Collapse
|
|
31
|
Mera-Ramírez A, Castillo A, Orobio Y, Gómez MA, Gallego-Marin C. Screening of TNFα, IL-10 and TLR4 single nucleotide polymorphisms in individuals with asymptomatic and chronic cutaneous leishmaniasis in Colombia: a pilot study. BMC Infect Dis 2017; 17:177. [PMID: 28241747 PMCID: PMC5330139 DOI: 10.1186/s12879-017-2281-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 02/22/2017] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Clinical manifestations of cutaneous leishmaniasis (CL) caused by Leishmania (Viannia) range from asymptomatic infection to self-limited, or chronic (non-healing) cutaneous lesions. Given the critical role of the immune response in the clinical outcome of CL, it is plausible that functional polymorphisms in immune-related genes contribute to define the clinical manifestations of human infection. METHODS DNA samples from a retrospective cohort of individuals from an endemic area of L. V. panamensis transmission in Colombia were used to determine the frequency of SNPs in TNFα, IL-10 and TLR4 genes. DNA samples were obtained from 74 adult participants: 38 patients presenting chronic cutaneous leishmaniasis (CCL) and 36 individuals with asymptomatic infection. Genotyping of TNFα-308G/A, IL-10-819C/T, and TLR4 Asp299Gly and Thr399Ile SNPs, was conducted by PCR-restriction fragment length polymorphisms. Allele, genotype frequencies and associations between SNPs and clinical groups were evaluated. RESULTS The A allele in TNFα-308G/A SNP was found more frequently in individuals with asymptomatic infection (16% vs 7%), whereas the CC genotype in IL-10-819 C/T SNP was more frequent in patients with CCL (34% vs. 27% in asymptomatic individuals). No differences in allele frequencies for TLR4 SNPs were found among groups. CONCLUSION This study provides a reference base for statistical power calculation and design of association studies of genetic polymorphisms in immune response related-genes and the pathogenesis of infections caused by L. V. panamensis.
Collapse
Affiliation(s)
- Angélica Mera-Ramírez
- Centro Internacional de Entrenamiento e Investigaciones Médicas-CIDEIM, Carrera 125 #, 19-225, Cali, Colombia
| | - Andrés Castillo
- Departamento de Biología. Facultad de Ciencias Naturales y Exactas, Universidad del Valle, Calle 13 No, 100-00, Cali, Colombia
| | - Yenifer Orobio
- Centro Internacional de Entrenamiento e Investigaciones Médicas-CIDEIM, Carrera 125 #, 19-225, Cali, Colombia
| | - María Adelaida Gómez
- Centro Internacional de Entrenamiento e Investigaciones Médicas-CIDEIM, Carrera 125 #, 19-225, Cali, Colombia
| | - Carolina Gallego-Marin
- Centro Internacional de Entrenamiento e Investigaciones Médicas-CIDEIM, Carrera 125 #, 19-225, Cali, Colombia. .,Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, 55 Lake Avenue North, 01655, Worcester, MA, USA.
| |
Collapse
|
|
32
|
Bader El Din NG, Farouk S, El-Shenawy R, Ibrahim MK, Dawood RM, Elhady MM, Salem AM, Zayed N, Khairy A, El Awady MK. Tumor necrosis factor-α -G308A polymorphism is associated with liver pathological changes in hepatitis C virus patients. World J Gastroenterol 2016; 22:7767-7777. [PMID: 27678360 PMCID: PMC5016377 DOI: 10.3748/wjg.v22.i34.7767] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Revised: 07/05/2016] [Accepted: 07/31/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the association of tumor necrosis factor alpha (TNFα) -G308A polymorphism with different liver pathological changes in treatment-naïve Egyptian patients infected with hepatitis C virus (HCV) genotype 4. METHODS This study included 180 subjects, composed of 120 treatment-naïve chronic HCV patients with different fibrosis grades (F0-F4) and 60 healthy controls. The TNFα -G308A region was amplified by PCR and the different genotypes were detected by restriction fragment length polymorphism analysis. The TNFα protein was detected by enzyme-linked immunosorbent assay. The influence of different TNFα -G308A genotypes on TNFα expression and liver disease progression were statistically analyzed. The OR and 95%CI were calculated to assess the relative risk confidence. RESULTS Current data showed that the TNFα -G308A SNP frequency was significantly different between controls and HCV infected patients (P = 0.001). Both the AA genotype and A allele were significantly higher in late fibrosis patients (F2-F4, n = 60) than in early fibrosis patients (F0-F1, n = 60) (P = 0.05, 0.04 respectively). Moreover, the GA or AA genotypes increased the TNFα serum level greater than the GG genotype (P = 0.002). The results showed a clear association between severe liver pathological conditions (inflammation, steatosis and fibrosis) and (GA + AA) genotypes (P = 0.035, 0.03, 0.04 respectively). The stepwise logistic regression analysis showed that the TNFα genotypes (GA + AA) were significantly associated with liver inflammation (OR = 3.776, 95%CI: 1.399-10.194, P = 0.009), severe steatosis (OR = 4.49, 95%CI: 1.441-14.0, P = 0.010) and fibrosis progression (OR = 2.84, 95%CI: 1.080-7.472, P = 0.034). Also, the A allele was an independent risk factor for liver inflammation (P = 0.003), steatosis (P = 0.003) and fibrosis (P = 0.014). CONCLUSION TNFα SNP at nucleotide -308 represents an important genetic marker that can be used for the prognosis of different liver pathological changes in HCV infected patients.
Collapse
|
|
33
|
Sbarsi I, Falcone C, Boiocchi C, Campo I, Zorzetto M, De Silvestri A, Cuccia M. Inflammation and Atherosclerosis: The Role of TNF and TNF Receptors Polymorphisms in Coronary Artery Disease. Int J Immunopathol Pharmacol 2016; 20:145-54. [PMID: 17346438 DOI: 10.1177/039463200702000117] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Inflammation plays an important role in the pathogenesis of atherosclerosis and coronary syndromes; moreover, various lines of evidence suggest that genetic factors contribute significantly to the risk of coronary artery disease (CAD). Through its effects on endothelial function, coagulation, insulin resistance and lipid metabolism, the proinflammatory cytokine TNF could be involved in cardiovascular pathophysiology. The aim of our study is to analyze whether TNF gene promoter (-308 G/A; −857 G/A) and TNF receptor polymorphisms (TNFR1 MspA1 I exon 1 and TNFR2 Nla III exon 6) show involvement in CAD predisposition in a group of Italian patients compared with healthy controls. Genotyping was performed by PCR-RFLP. Consecutive Italian patients with angiographically proven CAD (n= 248) were compared with controls (n=241), matched for age, sex and geographical origins. CAD patients showed a higher frequency of the TNF −308 A allele than healthy controls (p=0.046). After stratification according to risk factors for CAD, our analysis revealed that CAD patients with diabetes (p=0.042) and CAD patients without hypertension (p=0.0495) displayed a higher frequency of the TNF −308 AA genotype compared with healthy controls. Our data stress the inflammatory nature of CAD and show a possible involvement of TNF −308G/A promoter polymorphisms in the predisposition to the development of this disease. The less frequent A allele seems to be a predisposing factor for development of CAD in particular pathological settings associated with the disease itself, such as diabetes.
Collapse
Affiliation(s)
- I Sbarsi
- Department of Genetics and Microbiology, University of Pavia, Italy
| | | | | | | | | | | | | |
Collapse
|
|
34
|
Samaranayake N, Fernando SD, Neththikumara NF, Rodrigo C, Karunaweera ND, Dissanayake VHW. Association of HLA class I and II genes with cutaneous leishmaniasis: a case control study from Sri Lanka and a systematic review. BMC Infect Dis 2016; 16:292. [PMID: 27301744 PMCID: PMC4908677 DOI: 10.1186/s12879-016-1626-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 06/07/2016] [Indexed: 12/21/2022] Open
Abstract
Background The outcome of leishmaniasis is an interplay between Leishamania and the host. Identifying contributory host genetic factors is complicated by the variability in phenotype, ethnicity and parasite species. Leishmaniasis is caused exclusively by L. donovani in Sri Lanka with localized cutaneous leishmaniasis (LCL) being the predominant form. We report here an association study of human leucocyte antigen (HLA) class I and II genes with LCL in Sri Lanka, the first on HLA associations in cutaneous leishmaniasis in a South Asian population. Methods An existing DNA repository of 200 each of patients and controls was typed for HLA-DQ by PCR-SSP. Next generation sequencing-based typing for HLA-A, HLA-B and HLA-DRB1 alleles was done in a subset of 280 samples. Association tests were performed on 28,489 genotyped and imputed SNPs spanning a region of 1.4 Mb across the HLA genes. To compare our results with similar studies, we carried out a systematic review to document all HLA associations reported to-date for cutaneous and muco-cutaneous leishmaniasis. Results DRB1*04 DQB1*02 (P = 0.03; Pc = 0.09), DRB1*07 DQB1*02 (P = 0.03; Pc = 0.09) haplotypes were absent in patients. B*07 (P = 0.007; Pc = 0.13; OR = 0.36; 95 % CI = 0.17–0.77) allele and DRB1*15 DQB1*06 (P = 0.00; Pc < 0.01; OR = 0.3; 95 % CI = 0.2–.0.6) haplotype were over represented in controls and DRB1*15 (P = 0.002; Pc = 0.01) allele was over represented in patients. Two SNPs (rs281864595/rs1050517) in the antigen recognition region of HLA-B, comprised a haplotype more frequent in controls (P = 0.04). The alleles identified by the systematic review to predispose or to protect from cutaneous/mucocutaneous leishmaniasis remained highly heterogeneous in different populations studied. Conclusions Our preliminary findings suggest a role for some class I and class II HLA genes in determining predisposition to LCL in this population which should be corroborated with further studies. The systematic review reiterates this need, as the purported susceptibility or protection gained by certain HLA alleles or haplotypes has rarely been independently verified. Electronic supplementary material The online version of this article (doi:10.1186/s12879-016-1626-8) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Nilakshi Samaranayake
- Department of Parasitology, Faculty of Medicine, University of Colombo, 271, Kynsey Road, Colombo, 008, Sri Lanka
| | - Sumadhya D Fernando
- Department of Parasitology, Faculty of Medicine, University of Colombo, 271, Kynsey Road, Colombo, 008, Sri Lanka.
| | | | - Chaturaka Rodrigo
- Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Nadira D Karunaweera
- Department of Parasitology, Faculty of Medicine, University of Colombo, 271, Kynsey Road, Colombo, 008, Sri Lanka
| | | |
Collapse
|
|
35
|
Jin Y. Association of single nucleotide polymorphisms in tumor necrosis factor-alpha with cervical cancer susceptibility. Cell Biochem Biophys 2016; 71:77-84. [PMID: 25069725 DOI: 10.1007/s12013-014-0165-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Tumor necrosis factor-alpha (TNF-α) polymorphisms have been reported to play an important role in the development of cervical cancer. But the results remain inconclusive. We performed this study to provide a comprehensive assessment of the association by means of a meta-analysis in which all published studies were included. The studies investigating the associations between cervical cancer risk and TNF-α polymorphisms were identified through PubMed, Embase, CNKI, and Chinese BioMedical Literature Database. OR and 95% CI (odds ratio and 95% confidence interval) were calculated using either the fixed or random effects model to assess the associations. We eventually included eighteen case-control studies of SNP -308 G>A and nine studies of SNP -238 G>A. Meta-analysis of the former polymorphism suggested significantly increased risk of cervical cancer associated with the A allele (OR 1.19, 95% CI 1.02-1.38). Subgroup analysis according to ethnicity showed similar results in Caucasians (A vs. G: OR 1.25, 95% CI 1.02-1.54; AA vs. GG: OR 1.47, 95% CI 1.04-2.08; AA vs. GA+GG: OR 1.47, 95% CI 1.04-2.08). For SNP -238 G>A, a protective association was observed in overall comparisons (A vs. G: OR 0.64, 95% CI 0.51-0.80; AA+GA vs. GG: OR 0.62, 95% CI 0.49-0.79) and subgroup analysis of Caucasians (A vs. G: OR 0.67, 95% CI 0.53-0.83; AA+GA vs. GG: OR 0.65, 95% CI 0.51-0.82). Our meta-analysis indicates that TNF-α polymorphisms may confer susceptibility to cervical cancer in an ethic-specific fashion.
Collapse
Affiliation(s)
- Ying Jin
- Department of Obstetrics and Gynecology, Beijing Friendship Hospital, Capital Medical University, Beijing, China,
| |
Collapse
|
|
36
|
Lima-Junior JDC, Pratt-Riccio LR. Major Histocompatibility Complex and Malaria: Focus on Plasmodium vivax Infection. Front Immunol 2016; 7:13. [PMID: 26858717 PMCID: PMC4728299 DOI: 10.3389/fimmu.2016.00013] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 01/12/2016] [Indexed: 01/13/2023] Open
Abstract
The importance of host and parasite genetic factors in malaria resistance or susceptibility has been investigated since the middle of the last century. Nowadays, of all diseases that affect man, malaria still plays one of the highest levels of selective pressure on human genome. Susceptibility to malaria depends on exposure profile, epidemiological characteristics, and several components of the innate and adaptive immune system that influences the quality of the immune response generated during the Plasmodium lifecycle in the vertebrate host. But it is well known that the parasite's enormous capacity of genetic variation in conjunction with the host genetics polymorphism is also associated with a wide spectrum of susceptibility degrees to complicated or severe forms of the disease. In this scenario, variations in genes of the major histocompatibility complex (MHC) associated with host resistance or susceptibility to malaria have been identified and used as markers in host-pathogen interaction studies, mainly those evaluating the impact on the immune response, acquisition of resistance, or increased susceptibility to infection or vulnerability to disease. However, due to the intense selective pressure, number of cases, and mortality rates, the majority of the reported associations reported concerned Plasmodium falciparum malaria. Studies on the MHC polymorphism and its association with Plasmodium vivax, which is the most widespread Plasmodium and the most prevalent species outside the African continent, are less frequent but equally important. Despite punctual contributions, there are accumulated evidences of human genetic control in P. vivax infection and disease. Herein, we review the current knowledge in the field of MHC and derived molecules (HLA Class I, Class II, TNF-α, LTA, BAT1, and CTL4) regarding P. vivax malaria. We discuss particularly the results of P. vivax studies on HLA class I and II polymorphisms in relation to host susceptibility, naturally acquired immune response against specific antigens and the implication of this knowledge to overcome the parasite immune evasion. Finally, the potential impact of such polymorphisms on the development of vaccine candidate antigens against P. vivax will be studied.
Collapse
|
|
37
|
Potential Use of Interleukin-10 Blockade as a Therapeutic Strategy in Human Cutaneous Leishmaniasis. J Immunol Res 2015; 2015:152741. [PMID: 26495321 PMCID: PMC4606169 DOI: 10.1155/2015/152741] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Revised: 12/29/2014] [Accepted: 12/31/2014] [Indexed: 11/21/2022] Open
Abstract
Interleukin-10 overproduction has been associated with worse prognosis in human cutaneous leishmaniasis, while IFN-γ-dependent responses are associated with parasite killing and host protection. Innovative strategies are needed to overcome therapeutic failure observed in endemic areas. The use of monoclonal antibody-based immunotherapy targeting IL-10 cytokine was evaluated here. Partial IL-10 blockade in Leishmania braziliensis whole soluble antigen-stimulated cells from endemic area CL patients with active or healed lesions and asymptomatic controls was evaluated. Overall decrease in IL-10, IL-4, and TNF-α production was observed in all groups of subjects. Only patients with active lesions still produced some levels of TNF-α after anti-IL-10 stimulation in association with Leishmania antigens. Moreover, this strategy showed limited modulatory effects on IFN-γ-dependent chemokine CXCL10 production. Results suggest the potential immunotherapeutic use of partial IL-10 blockade in localized cutaneous leishmaniasis.
Collapse
|
|
38
|
Oliveira JB, Silva PCV, Vasconcelos LM, Gomes AV, Coêlho MRCD, Cahu GGOM, Muniz MTC, Domingues ALC. Influence of Polymorphism (-G308A) TNF-α on the Periportal Fibrosis Regression of Schistosomiasis After Specific Treatment. Genet Test Mol Biomarkers 2015; 19:598-603. [PMID: 26406299 DOI: 10.1089/gtmb.2015.0091] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
AIMS Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine and important mediator of severity for periportal fibrosis (PPF). We hypothesized that the (-G380A) polymorphism in the TNF-α gene is associated with regression of PPF after treatment for schistosomiasis mansoni. METHODS This is a retrospective cohort study, involving 124 Brazilian patients infected with Schistosoma mansoni, who were followed for 2 years after treatment to estimate the likelihood of PPF regression. Sociodemographic and clinical factors were also identified, with emphasis on specific treatment. RESULTS No statistical difference was observed between sociodemographic and clinical factors among the exposed groups. Genotypes (-308) GA/AA were positively associated with the degree of PFF regression (relative risk [RR] = 0.52; ρ = 0.025), as well as in the image pattern of PPF (RR = 0.56; ρ = 0.048), when compared with the genotype (-308) GG. There was no statistical difference in TNF-α serum levels between the exposed groups. CONCLUSIONS These results suggest that the (-G308A) polymorphism of the TNF-α gene may be one of the factors that prevents the regression of the degree and pattern of PPF in the Brazilian population, and thus it may potentially be a predictive factor of PPF intensity in schistosomiasis.
Collapse
Affiliation(s)
- Juliana B Oliveira
- 1 Gastroenterologia, Hospital das Clínicas , Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil
| | - Paula C V Silva
- 2 Centro Acadêmico de Vitória, Universidade Federal de Pernambuco , Vitória de Santo Antão, Pernambuco, Brazil .,3 Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica, Hospital Universitário Oswaldo Cruz , Universidade de Pernambuco, Recife, Pernambuco, Brazil
| | - Leticia M Vasconcelos
- 2 Centro Acadêmico de Vitória, Universidade Federal de Pernambuco , Vitória de Santo Antão, Pernambuco, Brazil
| | - Adriana V Gomes
- 3 Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica, Hospital Universitário Oswaldo Cruz , Universidade de Pernambuco, Recife, Pernambuco, Brazil .,4 Instituto de Ciências Biológicas, Universidade de Pernambuco , Recife, Pernambuco, Brazil
| | - Maria Rosãngela C D Coêlho
- 5 Setor de Virologia do Laboratório de Imunopatologia Keizo-Asami (LIKA), Universidade Federal de Pernambuco , Recife, Pernambuco, Brazil .,6 Departamento de Fisiologia e Farmacologia, Universidade Federal de Pernambuco , Recife, Pernambuco, Brazil
| | - Georgea G O M Cahu
- 5 Setor de Virologia do Laboratório de Imunopatologia Keizo-Asami (LIKA), Universidade Federal de Pernambuco , Recife, Pernambuco, Brazil
| | - Maria Tereza Cartaxo Muniz
- 3 Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica, Hospital Universitário Oswaldo Cruz , Universidade de Pernambuco, Recife, Pernambuco, Brazil .,4 Instituto de Ciências Biológicas, Universidade de Pernambuco , Recife, Pernambuco, Brazil .,7 Faculdade de Ciências Médicas, Universidade de Pernambuco , Recife, Pernambuco, Brazil
| | - Ana Lúcia C Domingues
- 8 Departamento de Medicina Clínica, Universidade Federal de Pernambuco , Recife, Pernambuco, Brazil
| |
Collapse
|
|
39
|
Fontes FL, de Araújo LF, Coutinho LG, Leib SL, Agnez-Lima LF. Genetic polymorphisms associated with the inflammatory response in bacterial meningitis. BMC MEDICAL GENETICS 2015; 16:70. [PMID: 26316174 PMCID: PMC4593216 DOI: 10.1186/s12881-015-0218-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 08/18/2015] [Indexed: 11/28/2022]
Abstract
Background Bacterial meningitis (BM) is an infectious disease that results in high mortality and morbidity. Despite efficacious antibiotic therapy, neurological sequelae are often observed in patients after disease. Currently, the main challenge in BM treatment is to develop adjuvant therapies that reduce the occurrence of sequelae. In recent papers published by our group, we described the associations between the single nucleotide polymorphisms (SNPs) AADAT +401C > T, APEX1 Asn148Glu, OGG1 Ser326Cys and PARP1 Val762Ala and BM. In this study, we analyzed the associations between the SNPs TNF -308G > A, TNF -857C > T, IL-8 -251A > T and BM and investigated gene-gene interactions, including the SNPs that we published previously. Methods The study was conducted with 54 BM patients and 110 healthy volunteers (as the control group). The genotypes were investigated via primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR) or polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analysis. Allelic and genotypic frequencies were also associated with cytokine and chemokine levels, as measured with the x-MAP method, and cell counts. We analyzed gene-gene interactions among SNPs using the generalized multifactor dimensionality reduction (GMDR) method. Results We did not find significant association between the SNPs TNF -857C > T and IL-8 -251A > T and the disease. However, a higher frequency of the variant allele TNF -308A was observed in the control group, associated with changes in cytokine levels compared to individuals with wild type genotypes, suggesting a possible protective role. In addition, combined inter-gene interaction analysis indicated a significant association between certain genotypes and BM, mainly involving the alleles APEX1 148Glu, IL8 -251 T and AADAT +401 T. These genotypic combinations were shown to affect cyto/chemokine levels and cell counts in CSF samples from BM patients. Conclusions In conclusion, this study revealed a significant association between genetic variability and altered inflammatory responses, involving important pathways that are activated during BM. This knowledge may be useful for a better understanding of BM pathogenesis and the development of new therapeutic approaches. Electronic supplementary material The online version of this article (doi:10.1186/s12881-015-0218-6) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Fabrícia Lima Fontes
- Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte, UFRN, Natal, Brazil.
| | - Luíza Ferreira de Araújo
- Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte, UFRN, Natal, Brazil.
| | - Leonam Gomes Coutinho
- Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte, UFRN, Natal, Brazil.
| | - Stephen L Leib
- Institute for Infectious Diseases, University of Bern, Friedbuehlstrasse 51, CH-3010, Bern, Switzerland.
| | - Lucymara Fassarella Agnez-Lima
- Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte, UFRN, Natal, Brazil. .,Departamento de Biologia Celular e Genética, Centro de Biociências - UFRN, Campus Universitário, Lagoa Nova, Natal, RN, 59078-970, Brazil.
| |
Collapse
|
|
40
|
Souza MA, Almeida TM, Castro MCAB, Oliveira-Mendes AP, Almeida AF, Oliveira BC, Rocha LF, Medeiros ACR, Brito MEF, Dessein AJJ, Pereira VRA. American tegumentary leishmaniasis: mRNA expression for Th1 and Treg mediators are predominant in patients with recent active disease. Immunobiology 2015; 221:253-9. [PMID: 26572279 DOI: 10.1016/j.imbio.2015.08.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Revised: 06/23/2015] [Accepted: 08/11/2015] [Indexed: 12/17/2022]
Abstract
Besides the Th1×Th2 paradigm, Treg and Th17 cytokines may play a role in the response to American tegumentary leishmaniasis. Considering the sensitivity and accuracy of qPCR and the lack of studies using this approach, we evaluated mRNA expression for IFN-γ, TNF-α, IL-4, IL-10, IL-6, IL-17A, IL-22, TGF-β, Foxp3 and RORC in peripheral blood mononuclear cells (PBMC) from patients with active disease, after stimulation with L. (V.) braziliensis soluble or insoluble fractions. Our results show that the antigens promoted specific mRNA expression related to the immune response in patients with ATL, and the insoluble fraction seems to stimulate the immune response in a higher intensity. The pro-inflammatory response was also fueled by IFN-γ and TNF-α, probably due to the active disease. IL-4, in certain way, seems to regulate this response along with IL-10 that may be produced by Treg cells, which are supposedly present in the patients' samples due the evidenced expression of Foxp3, in the presence of AgIns. In contrast, down-regulated RORC suggests that the significant levels of IL-6 expressed in response to AgSol were not able to induce an expressive Th17 profile along with TGF-β, which might have predominantly contributed to the development of a regulatory profile in the active disease.
Collapse
Affiliation(s)
- Marina A Souza
- Laboratory of Immunogenetics, Immunology Department, Aggeu Magalhães Research Center, Oswaldo Cruz Foundation (CPqAM/FIOCRUZ), Brazil.
| | - Thays M Almeida
- Laboratory of Immunogenetics, Immunology Department, Aggeu Magalhães Research Center, Oswaldo Cruz Foundation (CPqAM/FIOCRUZ), Brazil.
| | - Maria Carolina A B Castro
- Laboratory of Immunogenetics, Immunology Department, Aggeu Magalhães Research Center, Oswaldo Cruz Foundation (CPqAM/FIOCRUZ), Brazil.
| | - Andresa P Oliveira-Mendes
- Laboratory of Immunogenetics, Immunology Department, Aggeu Magalhães Research Center, Oswaldo Cruz Foundation (CPqAM/FIOCRUZ), Brazil.
| | - Amanda F Almeida
- Laboratory of Immunogenetics, Immunology Department, Aggeu Magalhães Research Center, Oswaldo Cruz Foundation (CPqAM/FIOCRUZ), Brazil.
| | - Beatriz C Oliveira
- Laboratory of Immunogenetics, Immunology Department, Aggeu Magalhães Research Center, Oswaldo Cruz Foundation (CPqAM/FIOCRUZ), Brazil.
| | - Lucas F Rocha
- Laboratory of Immunogenetics, Immunology Department, Aggeu Magalhães Research Center, Oswaldo Cruz Foundation (CPqAM/FIOCRUZ), Brazil.
| | - Angela C R Medeiros
- Hospital Universitário Oswaldo Cruz, Universidade de Pernambuco (HUOC/UPE), Brazil.
| | - Maria E F Brito
- Laboratory of Immunogenetics, Immunology Department, Aggeu Magalhães Research Center, Oswaldo Cruz Foundation (CPqAM/FIOCRUZ), Brazil.
| | - Alain J J Dessein
- Institut National de la Santé et la Recherche Médicale (INSERM-U906), France.
| | - Valéria R A Pereira
- Laboratory of Immunogenetics, Immunology Department, Aggeu Magalhães Research Center, Oswaldo Cruz Foundation (CPqAM/FIOCRUZ), Brazil.
| |
Collapse
|
|
41
|
Tavares MCM, de Lima Júnior SF, Coelho AVC, Marques TRNM, de Araújo DHT, Heráclio SDA, Amorim MMR, de Souza PRE, Crovella S. Tumor necrosis factor (TNF) alpha and interleukin (IL) 18 genes polymorphisms are correlated with susceptibility to HPV infection in patients with and without cervical intraepithelial lesion. Ann Hum Biol 2015; 43:261-8. [DOI: 10.3109/03014460.2014.1001436] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
| | | | - Antonio V. C. Coelho
- Department of Genetics, Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil,
| | | | | | | | - Melânia M. Ramos Amorim
- Maternal and Child Healthcare Departament, Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife, PE, Brazil, and
| | | | - Sergio Crovella
- Department of Genetics, Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil,
| |
Collapse
|
|
42
|
Ejghal R, Hamdi S, Idrissi M, Hida M, Hessni AE, Lemrani M. Polymorphisms in tumor necrosis factor genes and susceptibility to visceral leishmaniasis in Moroccan children. ASIAN PACIFIC JOURNAL OF TROPICAL DISEASE 2015. [DOI: 10.1016/s2222-1808(14)60801-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
|
|
43
|
Association of leishmaniasis with TNF alpha promoter and SLC11A1 gene polymorphisms in patients of two endemic areas in Mexico. Microbes Infect 2015; 17:387-94. [PMID: 25603101 DOI: 10.1016/j.micinf.2015.01.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Revised: 12/02/2014] [Accepted: 01/12/2015] [Indexed: 11/24/2022]
Abstract
Some Single Nucleotide Polymorphisms (SNPs) of interleukins and other modulatory molecules of the immune response play an important role in susceptibility to infectious diseases, particularly those involving intracellular parasites. In this study, we evaluated allele, genotype and haplotype associations of two SNPs of the TNF-α promoter and seven of the SLC11A1 gene in 79 patients with localized cutaneous leishmaniasis (CL) and 15 with visceral leishmaniasis (VL), compared with 127 and 89 locality paired controls, respectively, from two endemic areas of Chiapas State, Mexico. None of the TNF-α alleles and genotypes was associated either to CL or to VL. Alleles rs2276631-C (P = 0.02; OR [95%CI] = 2.11 [1.16-3.86]) and rs2279015-G (P = 0.005; OR [95%CI] = 2.42 [1.33-4.41]) of SLC11A1, were associated with susceptibility to VL, whereas genotypes rs2276631 C/C (P = 0.003; OR [95%CI] = 2.65 [1.41-5.00]) and rs2279015 G/G (P = 0.018; OR [95%CI] = 2.05 [1.15-3.64]) were significantly increased in CL and VL patients, respectively. Complete haplotypes involved in susceptibility were CGCCGDins with VL and CGCCADins with CL. CGCCA was the minimal susceptibility haplotype for CL and CCG for VL. Our data suggest that SLC11A1 gene polymorphisms might have a relevant role in the pathology of leishmaniasis, directing towards susceptibility outcome of this disease in residents of an endemic area.
Collapse
|
|
44
|
Prenatal exposure to arsenic and cadmium impacts infectious disease-related genes within the glucocorticoid receptor signal transduction pathway. Int J Mol Sci 2014; 15:22374-91. [PMID: 25479081 PMCID: PMC4284714 DOI: 10.3390/ijms151222374] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 11/04/2014] [Accepted: 11/26/2014] [Indexed: 01/27/2023] Open
Abstract
There is increasing evidence that environmental agents mediate susceptibility to infectious disease. Studies support the impact of prenatal/early life exposure to the environmental metals inorganic arsenic (iAs) and cadmium (Cd) on increased risk for susceptibility to infection. The specific biological mechanisms that underlie such exposure-mediated effects remain understudied. This research aimed to identify key genes/signal transduction pathways that associate prenatal exposure to these toxic metals with changes in infectious disease susceptibility using a Comparative Genomic Enrichment Method (CGEM). Using CGEM an infectious disease gene (IDG) database was developed comprising 1085 genes with known roles in viral, bacterial, and parasitic disease pathways. Subsequently, datasets collected from human pregnancy cohorts exposed to iAs or Cd were examined in relationship to the IDGs, specifically focusing on data representing epigenetic modifications (5-methyl cytosine), genomic perturbations (mRNA expression), and proteomic shifts (protein expression). A set of 82 infection and exposure-related genes was identified and found to be enriched for their role in the glucocorticoid receptor signal transduction pathway. Given their common identification across numerous human cohorts and their known toxicological role in disease, the identified genes within the glucocorticoid signal transduction pathway may underlie altered infectious disease susceptibility associated with prenatal exposures to the toxic metals iAs and Cd in humans.
Collapse
|
|
45
|
Nogueira RS, Gomes-Silva A, Bittar RC, Silva Mendonça D, Amato VS, da Silva Mattos M, Oliveira-Neto MP, Coutinho SG, Da-Cruz AM. Antigen-triggered interferon-γ and interleukin-10 pattern in cured mucosal leishmaniasis patients is shaped during the active phase of disease. Clin Exp Immunol 2014; 177:679-86. [PMID: 24773586 PMCID: PMC4137852 DOI: 10.1111/cei.12364] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2014] [Indexed: 11/28/2022] Open
Abstract
An exacerbated type 1 response to leishmanial antigens is the basis of tissue destruction observed in mucosal leishmaniasis (ML). After therapy, a persistent production of high levels of inflammatory cytokines can confer a poor prognosis. Herein we investigated whether the clinical conditions defined during the active phase of ML affect the magnitude of long-term anti-Leishmania immune response. Twenty clinically cured ML cases were studied. Peripheral blood mononuclear cells (PBMC) were cultured with L. braziliensis antigens (Lb-Ag), Toxoplasma gondii antigens (Tg-Ag), concanavalin-A (Con-A) or medium alone, and the lymphocyte proliferative response and cytokine secretion were quantified. Medical records were reviewed for Montenegro skin test (MST) during diagnosis, duration of ML disease or time elapsed after clinical cure. The duration of disease was correlated positively with MST (r = 0·61). Lb-Ag induced interferon (IFN)-γ was correlated positively with duration of illness (r = 0·69) as well as the frequency of secreting cells [enzyme-linked immunospot (ELISPOT)] assay. No association was observed for Tg-Ag or Con-A. Disease duration was correlated negatively with interleukin (IL)-10 production (r = −0·76). Moreover, a negative correlation between length of time after clinical cure and TNF levels (r = −0·94) or the IFN-γ : IL-10 ratio (r = −0·89) were also seen. We suggest that the magnitude of the IFN-γ inflammatory response triggered by ML can be driven by the time of leishmanial antigens exposition during the active phase of the disease. This pattern could persist even long-term after cure. However, despite IFN-γ levels, the decrease of the TNF and IFN-γ : IL-10 ratio reflects the control of proinflammatory responses achieved by cure of ML, possibly preventing disease relapses.
Collapse
Affiliation(s)
- R S Nogueira
- Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil
| | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Vu D, Shah T, Ansari J, Sakharkar P, Yasir Q, Naraghi R, Hutchinson I, Min D. Interferon-gamma gene polymorphism +874 A/T is associated with an increased risk of cytomegalovirus infection among Hispanic renal transplant recipients. Transpl Infect Dis 2014; 16:724-32. [DOI: 10.1111/tid.12285] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Revised: 04/25/2014] [Accepted: 06/21/2014] [Indexed: 11/30/2022]
Affiliation(s)
- D. Vu
- Mendez National Institute of Transplantation; Los Angeles California USA
- Western University of Health Sciences; Pomona California USA
- Transplant Research Institute; Los Angeles California USA
- St. Vincent Medical Center; Los Angeles California USA
| | - T. Shah
- Western University of Health Sciences; Pomona California USA
- Transplant Research Institute; Los Angeles California USA
- St. Vincent Medical Center; Los Angeles California USA
- University of Southern California; Los Angeles California USA
| | - J. Ansari
- Western University of Health Sciences; Pomona California USA
| | - P. Sakharkar
- Roosevelt University College of Pharmacy; Schaumburg Illinois USA
| | - Q. Yasir
- Roosevelt University College of Pharmacy; Schaumburg Illinois USA
| | - R. Naraghi
- Transplant Research Institute; Los Angeles California USA
- St. Vincent Medical Center; Los Angeles California USA
| | - I. Hutchinson
- Mendez National Institute of Transplantation; Los Angeles California USA
- University of Southern California; Los Angeles California USA
| | - D. Min
- Western University of Health Sciences; Pomona California USA
- St. Vincent Medical Center; Los Angeles California USA
| |
Collapse
|
|
47
|
Hartley MA, Drexler S, Ronet C, Beverley SM, Fasel N. The immunological, environmental, and phylogenetic perpetrators of metastatic leishmaniasis. Trends Parasitol 2014; 30:412-22. [PMID: 24954794 DOI: 10.1016/j.pt.2014.05.006] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Revised: 05/23/2014] [Accepted: 05/24/2014] [Indexed: 02/07/2023]
Abstract
Cutaneous leishmaniases have persisted for centuries as chronically disfiguring parasitic infections affecting millions of people across the subtropics. Symptoms range from the more prevalent single, self-healing cutaneous lesion to a persistent, metastatic disease, where ulcerations and granulomatous nodules can affect multiple secondary sites of the skin and delicate facial mucosa, even sometimes diffusing throughout the cutaneous system as a papular rash. The basis for such diverse pathologies is multifactorial, ranging from parasite phylogeny to host immunocompetence and various environmental factors. Although complex, these pathologies often prey on weaknesses in the innate immune system and its pattern recognition receptors. This review explores the observed and potential associations among the multifactorial perpetrators of infectious metastasis and components of the innate immune system.
Collapse
Affiliation(s)
- Mary-Anne Hartley
- Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland
| | - Stefan Drexler
- Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland
| | - Catherine Ronet
- Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland
| | - Stephen M Beverley
- Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO, USA
| | - Nicolas Fasel
- Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
| |
Collapse
|
|
48
|
Castellucci LC, Almeida LFD, Jamieson SE, Fakiola M, Carvalho EMD, Blackwell JM. Host genetic factors in American cutaneous leishmaniasis: a critical appraisal of studies conducted in an endemic area of Brazil. Mem Inst Oswaldo Cruz 2014; 109:279-88. [PMID: 24863979 PMCID: PMC4131779 DOI: 10.1590/0074-0276140028] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 04/07/2014] [Indexed: 12/17/2022] Open
Abstract
American cutaneous leishmaniasis (ACL) is a vector-transmitted infectious disease with an estimated 1.5 million new cases per year. In Brazil, ACL represents a significant public health problem, with approximately 30,000 new reported cases annually, representing an incidence of 18.5 cases per 100,000 inhabitants. Corte de Pedra is in a region endemic for ACL in the state of Bahia (BA), northeastern Brazil, with 500-1,300 patients treated annually. Over the last decade, population and family-based candidate gene studies were conducted in Corte de Pedra, founded on previous knowledge from studies on mice and humans. Notwithstanding limitations related to sample size and power, these studies contribute important genetic biomarkers that identify novel pathways of disease pathogenesis and possible new therapeutic targets. The present paper is a narrative review about ACL immunogenetics in BA, highlighting in particular the interacting roles of the wound healing gene FLI1 with interleukin-6 and genes SMAD2 and SMAD3 of the transforming growth factor beta signalling pathway. This research highlights the need for well-powered genetic and functional studies on Leishmania braziliensis infection as essential to define and validate the role of host genes in determining resistance/susceptibility regarding this disease.
Collapse
Affiliation(s)
- Léa Cristina Castellucci
- Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais, Universidade Federal da Bahia, Salvador, BA, Brasil
| | - Lucas Frederico de Almeida
- Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais, Universidade Federal da Bahia, Salvador, BA, Brasil
| | | | - Michaela Fakiola
- Telethon Kids Institute, The University of Western Australi, Perth, Australia
| | - Edgar Marcelino de Carvalho
- Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais, Universidade Federal da Bahia, Salvador, BA, Brasil
| | | |
Collapse
|
|
49
|
High producer haplotype (CAG) of -863C/A, -308G/A and -238G/A polymorphisms in the promoter region of TNF-α gene associate with enhanced apoptosis of lymphocytes in HIV-1 subtype C infected individuals from North India. PLoS One 2014; 9:e98020. [PMID: 24837009 PMCID: PMC4024031 DOI: 10.1371/journal.pone.0098020] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Accepted: 04/26/2014] [Indexed: 12/23/2022] Open
Abstract
Introduction The natural history of HIV-1 infection and its progression towards AIDS vary considerably among individuals. Host genetic factors may be one of the possible reasons for variable HIV-1 disease progression. Single nucleotide polymorphisms (SNPs) in the promoter region of TNF-α gene can influence its production. The aim of the present study was to determine the association of functional TNF-α SNPs and its associated parameters related to apoptosis that may influence the rate of HIV-1 disease progression. Methods Therapy naive, 100 HIV slow progressors (SPs), 100 HIV fast progressors (FPs), 50 HIV exposed but seronegative individuals (ESNs) and 260 healthy controls from same ethnic origin were recruited. Genotyping of TNF-α variants (−863C/A, -308G/A and -238G/A) was done using PCR-RFLP. CD4 counts were determined by flow cytometry. Plasma viral load was estimated by COBAS AMPLICOR HIV-1 monitor test. Plasma TNF-α concentration was estimated by Human CBA Th1/Th2 cytokine kit. The lymphocyte mitochondrial membrane potential was measured by JC-1 dye by flow cytometry. Results Genotype and allele frequency of TNF-α -238G/A and -863C/A was not significantly different in HIV-1-infected patients when compared to controls, while that of TNF-α -308G/A variant (high TNF-α producer) was significantly higher in FPs compared to SPs (p<0.01, OR = 3.43). Haplotype analyses also showed that carriers of high TNF-α producing haplotype CAG was significantly more common among FPs compared to SPs (p<0.01, OR = 3). The circulating TNF-α levels in blood also correlated well with genotypes. The lymphocyte mitochondrial membrane potential of FPs having CAG haplotype was significantly low as compared to wild type (CGG) haplotype (417±22 vs 571±28, p<0.01). Conclusion High producer haplotype, CAG of TNF-α gene associates with enhanced apoptosis of lymphocytes in HIV-1 infected individuals, hence faster progression to AIDS. However, further functional studies are needed to confirm this association and this knowledge may help clinicians to better understand the disease outcome.
Collapse
|
|
50
|
Ives A, Masina S, Castiglioni P, Prével F, Revaz-Breton M, Hartley MA, Launois P, Fasel N, Ronet C. MyD88 and TLR9 dependent immune responses mediate resistance to Leishmania guyanensis infections, irrespective of Leishmania RNA virus burden. PLoS One 2014; 9:e96766. [PMID: 24801628 PMCID: PMC4011865 DOI: 10.1371/journal.pone.0096766] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Accepted: 04/11/2014] [Indexed: 12/20/2022] Open
Abstract
Infections with Leishmania parasites of the Leishmania Viannia subgenus give rise to both localized cutaneous (CL), and metastatic leishmaniasis. Metastasizing disease forms including disseminated (DCL) and mutocutaneous (MCL) leishmaniasis result from parasitic dissemination and lesion formation at sites distal to infection and have increased inflammatory responses. The presence of Leishmania RNA virus (LRV) in L. guyanensis parasites contributes to the exacerbation of disease and impacts inflammatory responses via activation of TLR3 by the viral dsRNA. In this study we investigated other innate immune response adaptor protein modulators and demonstrated that both MyD88 and TLR9 played a crucial role in the development of Th1-dependent healing responses against L. guyanensis parasites regardless of their LRV status. The absence of MyD88- or TLR9-dependent signaling pathways resulted in increased Th2 associated cytokines (IL-4 and IL-13), which was correlated with low transcript levels of IL-12p40. The reliance of IL-12 was further confirmed in IL12AB−/− mice, which were completely susceptible to infection. Protection to L. guyanensis infection driven by MyD88- and TLR9-dependent immune responses arises independently to those induced due to high LRV burden within the parasites.
Collapse
Affiliation(s)
- Annette Ives
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Slavica Masina
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Patrik Castiglioni
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Florence Prével
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Mélanie Revaz-Breton
- Department of Biochemistry, World Health Organization Immunology Research and Training center (WHO-IRTC), Epalinges, Switzerland
| | - Mary-Anne Hartley
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Pascal Launois
- Department of Biochemistry, World Health Organization Immunology Research and Training center (WHO-IRTC), Epalinges, Switzerland
| | - Nicolas Fasel
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Catherine Ronet
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
- Department of Biochemistry, World Health Organization Immunology Research and Training center (WHO-IRTC), Epalinges, Switzerland
- * E-mail:
| |
Collapse
|