title: NOD2-RIP2-Mediated Signaling Helps Shape Adaptive Immunity in Visceral Leishmaniasis.
abstract: Interferon γ (IFN-γ) and interleukin 17A (IL-17A)-producing cells are described to be related to the protection against Leishmania infantum infection. How the immune system coordinates the balance between T-helper type 1 (Th1) and 17 (Th17) responses during visceral leishmaniasis (VL) is still unknown. Here, we combined transcriptional profiling, using RNA sequencing analysis of human samples, with an experimental model to show that Th17-related genes are suppressed and that Th1 signature genes are induced during human VL. The high amount of Th1 cells in VL was dependent on the NOD2-RIP2 signaling in dendritic cells, which was crucial for interleukin 12 production through the phosphorylation of MAPK. On the other hand, this pathway inhibits Th17 cells by limiting interleukin 23 production. As a consequence, Nod2-/-and Rip2-/-mice showed defects in Th1 responses and higher parasite loads as compared to WT mice. Together, the data demonstrate that the NOD2-RIP2 pathway is activated in murine and human VL and plays a role in shaping adaptive immunity toward a Th1 profile.
authors.affiliation: Department of Biochemistry, Immunology, and Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto.|Edmond and Lily Safra International Institute of Neuroscience, Macaíba.
authors.forename: Manuela S L
authors.initials: MS
authors.lastname: Nascimento
authors.affiliation: Department of Biochemistry, Immunology, and Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto.
authors.forename: Marcela D
authors.initials: MD
authors.lastname: Ferreira
authors.affiliation: Department of Biochemistry, Immunology, and Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto.
authors.forename: Gustavo F S
authors.initials: GF
authors.lastname: Quirino
authors.affiliation: Department of Biochemistry, Immunology, and Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto.
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Maruyama
authors.affiliation: Respiratory, Inflammation, and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca, Mölndal, Sweden.
authors.forename: Jayendra K
authors.initials: JK
authors.lastname: Krishnaswamy
authors.affiliation: Department of Laboratory Medicine.|Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, Immunology, and Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto.
authors.forename: Jonilson
authors.initials: J
authors.lastname: Berlink
authors.affiliation: Department of Biochemistry, Immunology, and Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Fonseca
authors.affiliation: Department of Biochemistry, Immunology, and Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto.
authors.forename: Dario S
authors.initials: DS
authors.lastname: Zamboni
authors.affiliation: Department of Biochemistry, Immunology, and Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Carregaro
authors.affiliation: Department of Medicine, University Hospital, Federal University of Sergipe, Aracaju, Brazil.
authors.forename: Roque P
authors.initials: RP
authors.lastname: Almeida
authors.affiliation: Department of Biochemistry, Immunology, and Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.affiliation: Department of Laboratory Medicine.|Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Eisenbarth
authors.affiliation: Department of Biochemistry, Immunology, and Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto.
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D007898:Leishmaniasis, Visceral / Q000276:immunology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism*; D059208:Parasite Load; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse
keywords: Leishmania infatum; NOD2; RIP2; adaptive immunity; dendritic cells; visceral leishmaniasis