title: Genome-Wide Association Study of Cell-Mediated Response in Dogs Naturally Infected by Leishmania infantum.
abstract: A genome-wide association study (GWAS) could unravel the complexity of the cell-mediated immunity (CMI) to canine leishmaniasis (CanL). Therefore, we scanned 110,165 single-nucleotide polymorphisms (SNPs), aiming to identify chromosomal regions associated with the leishmanin skin test (LST), lymphocyte proliferation assay (LPA), and cytokine responses to further understand the role played by CMI in the outcome of natural Leishmania infantum infection in 189 dogs. Based on LST and LPA, four CMI profiles were identified (LST-/LPA-, LST+/LPA-, LST-/LPA+, and LST+/LPA+), which were not associated with subclinically infected or diseased dogs. LST+/LPA+dogs showed increased interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) levels and mild parasitism in the lymph nodes, whereas LST-/LPA+dogs, in spite of increased IFN-γ, also showed increased interleukin-10 (IL-10) and transforming growth factor β (TGF-β) levels and the highest parasite load in lymph nodes. Low T cell proliferation under low parasite load suggested that L. infantum was not able to induce effective CMI in the early stage of infection. Altogether, genetic markers explained 87%, 16%, 15%, 11%, 0%, and 0% of phenotypic variance in TNF-α, TGF-β, LST, IL-10, IFN-γ, and LPA, respectively. GWAS showed that regions associated with TNF-α include the following genes: IL12RB1, JAK3, CCRL2, CCR2, CCR3, and CXCR6, involved in cytokine and chemokine signaling; regions associated with LST, including COMMD5 and SHARPIN, involved in regulation of NF-κB signaling; and regions associated with IL-10, including LTBP1 and RASGRP3, involved in T regulatory lymphocytes differentiation. These findings pinpoint chromosomic regions related to the cell-mediated response that potentially affect the clinical complexity and the parasite replication in canine L. infantum infection.
authors.affiliation: Departamento de Patologia Veterinária, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, Brazil.|Laboratório de Patologia de Doenças Infecciosas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Luís F S
authors.initials: LF
authors.lastname: Batista
authors.affiliation: Universidade Estadual Paulista, Departamento de Medicina Veterinária Preventiva e Reprodução Animal, Faculdade de Ciências Agrárias e Veterinárias, Jaboticabal, São Paulo, Brazil.
authors.forename: Yuri T
authors.initials: YT
authors.lastname: Utsunomiya
authors.affiliation: Laboratório de Patologia de Doenças Infecciosas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Thaís B F
authors.initials: TB
authors.lastname: Silva
authors.affiliation: Laboratório de Patologia de Doenças Infecciosas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Raíssa A
authors.initials: RA
authors.lastname: Dias
authors.affiliation: Laboratório de Patologia de Doenças Infecciosas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Thaise Y
authors.identifier: http://orcid.org/0000-0002-1431-6829
authors.initials: TY
authors.lastname: Tomokane
authors.affiliation: Universidade Estadual Paulista, Departamento de Clínica, Cirurgia e Reprodução Animal, Faculdade de Medicina Veterinária, Araçatuba, São Paulo, Brazil.
authors.forename: Acácio D
authors.initials: AD
authors.lastname: Pacheco
authors.affiliation: Laboratório de Patologia de Doenças Infecciosas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Vânia L R
authors.initials: VL
authors.lastname: da Matta
authors.affiliation: Laboratório de Patologia de Doenças Infecciosas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.|Deparatmento de Parasitologia, Instituto Evandro Chagas, Ananindeua, Pará, Brazil.
authors.forename: Fernando T
authors.initials: FT
authors.lastname: Silveira
authors.affiliation: Universidade Estadual Paulista, Departamento de Clínica, Cirurgia e Reprodução Animal, Faculdade de Medicina Veterinária, Araçatuba, São Paulo, Brazil.
authors.forename: Mary
authors.initials: M
authors.lastname: Marcondes
authors.affiliation: Universidade Estadual Paulista, Departmento de Saúde Animal e Produção, Faculdade de Medicina Veterinária, Araçatuba, São Paulo, Brazil.
authors.forename: Cáris M
authors.initials: CM
authors.lastname: Nunes
authors.affiliation: Laboratório de Patologia de Doenças Infecciosas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil mdlauren@usp.br.
authors.forename: Márcia D
authors.initials: MD
authors.lastname: Laurenti
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004283:Dog Diseases / Q000378:metabolism / Q000469:parasitology*; D004285:Dogs; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D055106:Genome-Wide Association Study; D007111:Immunity, Cellular / Q000502:physiology*; D018314:Leishmania infantum; D007898:Leishmaniasis, Visceral / Q000378:metabolism / Q000662:veterinary*; D008214:Lymphocytes / Q000502:physiology; D008297:Male; D012882:Skin Tests / Q000662:veterinary
chemical_list: D016207:Cytokines