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      Single nucleotide polymorphisms of the genes IL-2, IL-2RB, and JAK3 in patients with cutaneous leishmaniasis caused by Leishmania (V.) guyanensis in Manaus, Amazonas, Brazil

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          Abstract

          Leishmaniasis is a disease caused by intracellular protozoan parasites of the genus Leishmania. In endemic areas, only a portion of exposed subjects develops cutaneous leishmaniasis (CL), suggesting that the genetic inheritance of the host plays a vital role in both resistance and susceptibility to the disease. Interleukin-2 (IL-2) is a cytokine that plays a central role in the regulation of the immune response in infection through the axis IL-2/IL-2R (receptor) complex, triggering a series of intracellular events, among which the signaling of Janus kinase/signal transducers and activators of transcription (JAK-STAT). The present study aimed at verifying the possible relationship between single nucleotide polymorphism (s) (SNP s) in the genes IL-2, IL-2RB, and JAK3 in subjects with CL caused by Leishmania guyanensis in the city of Manaus, state of Amazonas, Brazil. 820 patients with CL and 850 healthy subjects (control group) coming from the same endemic areas as the patients were examined. The SNPs -2425G/A (rs4833248) and -330 T/G (rs2069762), located in the IL-2 gene promoter region, seem to influence the expression of the gene and the SNP +10558G/A (rs1003694) and +13295T/C (rs3212760) located in the 3rd intron of the IL-2RB gene and the 13th intron of the JAK3 gene, respectively, were studied by PCR-RFLP. Genotypes and alleles frequencies were obtained by direct counting. For the comparison between the two groups, the χ2 test with OR (odds ratio) and the 95% confidence interval (CI) were used. Similar genotypes and alleles frequencies for the different SNPs were observed in both patients with CL and healthy controls. Comparison of genotypic and allelic frequency between patients with CL and healthy subjects did not show any difference. These polymorphisms do not predict susceptibility to, or protection against the development of CL caused by L. guyanensis in the Amazonas.

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          CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity.

          The long-term persistence of pathogens in a host that is also able to maintain strong resistance to reinfection, referred to as concomitant immunity, is a hallmark of certain infectious diseases, including tuberculosis and leishmaniasis. The ability of pathogens to establish latency in immune individuals often has severe consequences for disease reactivation. Here we show that the persistence of Leishmania major in the skin after healing in resistant C57BL/6 mice is controlled by an endogenous population of CD4+CD25+ regulatory T cells. These cells constitute 5-10% of peripheral CD4+ T cells in naive mice and humans, and suppress several potentially pathogenic responses in vivo, particularly T-cell responses directed against self-antigens. During infection by L. major, CD4+CD25+ T cells accumulate in the dermis, where they suppress-by both interleukin-10-dependent and interleukin-10-independent mechanisms-the ability of CD4+CD25- effector T cells to eliminate the parasite from the site. The sterilizing immunity achieved in mice with impaired IL-10 activity is followed by the loss of immunity to reinfection, indicating that the equilibrium established between effector and regulatory T cells in sites of chronic infection might reflect both parasite and host survival strategies.
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            Leishmaniasis: a review

            Leishmaniasis is caused by an intracellular parasite transmitted to humans by the bite of a sand fly. It is endemic in Asia, Africa, the Americas, and the Mediterranean region. Worldwide, 1.5 to 2 million new cases occur each year, 350 million are at risk of acquiring the disease, and leishmaniasis causes 70,000 deaths per year. Clinical features depend on the species of Leishmania involved and the immune response of the host. Manifestations range from the localized cutaneous to the visceral form with potentially fatal outcomes. Many drugs are used in its treatment, but the only effective treatment is achieved with current pentavalent antimonials.
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              STrengthening the REporting of Genetic Association Studies (STREGA)— An Extension of the STROBE Statement

              Julian Little and colleagues present the STREGA recommendations, which are aimed at improving the reporting of genetic association studies.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: MethodologyRole: Writing – original draft
                Role: Data curationRole: Methodology
                Role: Data curationRole: Formal analysisRole: MethodologyRole: Validation
                Role: Data curationRole: Formal analysisRole: MethodologyRole: Validation
                Role: Data curationRole: Formal analysisRole: Methodology
                Role: Writing – original draft
                Role: ConceptualizationRole: Formal analysisRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                8 August 2019
                2019
                : 14
                : 8
                : e0220572
                Affiliations
                [1 ] Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus, Amazonas, Brazil
                [2 ] Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Amazonas, Brazil
                [3 ] Programa de Pós-graduação de Imunologia Básica, Universidade Federal do Amazonas, Manaus, Brazil
                [4 ] Post-Graduation Department, Nilton Lins University, Manaus, Amazonas, Brazil
                [5 ] Department of Food Technology, Instituto Nacional de Pesquisas da Amazônia (INPA), Manaus, Amazonas, Brazil
                [6 ] Faculdade de Medicina, Nilton Lins University, Manaus, Amazonas, Brazil
                King Saud University, SAUDI ARABIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-7922-6090
                http://orcid.org/0000-0002-0538-0773
                Article
                PONE-D-19-06868
                10.1371/journal.pone.0220572
                6687158
                31393896
                76ad1987-5211-41dd-8094-e0bcd4520141
                © 2019 de Araújo Santos et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 8 March 2019
                : 18 July 2019
                Page count
                Figures: 0, Tables: 3, Pages: 10
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100003593, Conselho Nacional de Desenvolvimento Científico e Tecnológico;
                Award ID: 404181/2012-0
                Award Recipient :
                Funded by: FAPEAM
                Award ID: 062.01954/2015
                Award Recipient :
                This work was supported by the Brazilian Council for Scientific and Technological Development (CNPq) to RR (grant number: 404181/2012-0) and the Fundação de Amparo a Pesquisa do Estado do Amazonas to RR (grant number: 062.01954/2015). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Tropical Diseases
                Neglected Tropical Diseases
                Leishmaniasis
                Medicine and Health Sciences
                Parasitic Diseases
                Protozoan Infections
                Leishmaniasis
                Medicine and Health Sciences
                Infectious Diseases
                Zoonoses
                Leishmaniasis
                Biology and Life Sciences
                Organisms
                Eukaryota
                Protozoans
                Parasitic Protozoans
                Leishmania
                People and places
                Geographical locations
                South America
                Brazil
                Biology and Life Sciences
                Genetics
                Heredity
                Genetic Mapping
                Variant Genotypes
                Medicine and Health Sciences
                Parasitic Diseases
                Biology and Life Sciences
                Physiology
                Immune Physiology
                Cytokines
                Medicine and Health Sciences
                Physiology
                Immune Physiology
                Cytokines
                Biology and Life Sciences
                Immunology
                Immune System
                Innate Immune System
                Cytokines
                Medicine and Health Sciences
                Immunology
                Immune System
                Innate Immune System
                Cytokines
                Biology and Life Sciences
                Developmental Biology
                Molecular Development
                Cytokines
                People and Places
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                Europe
                Biology and Life Sciences
                Genetics
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                All relevant data are within the paper and its Supporting Information files.

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