title: Cynomolgus macaques naturally infected with Trypanosoma cruzi-I exhibit an overall mixed pro-inflammatory/modulated cytokine signature characteristic of human Chagas disease.
abstract: Non-human primates have been shown to be useful models for Chagas disease. We previously reported that natural T. cruzi infection of cynomolgus macaques triggers clinical features and immunophenotypic changes of peripheral blood leukocytes resembling those observed in human Chagas disease. In the present study, we further characterize the cytokine-mediated microenvironment to provide supportive evidence of the utility of cynomolgus macaques as a model for drug development for human Chagas disease.
  
  
  
  In this cross-sectional study design, flow cytometry and systems biology approaches were used to characterize the ex vivo and in vitro T. cruzi-specific functional cytokine signature of circulating leukocytes from TcI-T. cruzi naturally infected cynomolgus macaques (CH). Results showed that CH presented an overall CD4+-derived IFN-γ pattern regulated by IL-10-derived from CD4+ T-cells and B-cells, contrasting with the baseline profile observed in non-infected hosts (NI). Homologous TcI-T. cruzi-antigen recall in vitro induced a broad pro-inflammatory cytokine response in CH, mediated by TNF from innate/adaptive cells, counterbalanced by monocyte/B-cell-derived IL-10. TcIV-antigen triggered a more selective cytokine signature mediated by NK and T-cell-derived IFN-γ with modest regulation by IL-10 from T-cells. While NI presented a cytokine network comprised of small number of neighborhood connections, CH displayed a complex cross-talk amongst network elements. Noteworthy, was the ability of TcI-antigen to drive a complex global pro-inflammatory network mediated by TNF and IFN-γ from NK-cells, CD4+ and CD8+ T-cells, regulated by IL-10+CD8+ T-cells, in contrast to the TcIV-antigens that trigger a modest network, with moderate connecting edges.
  
  
  
  Altogether, our findings demonstrated that CH present a pro-inflammatory/regulatory cytokine signature similar to that observed in human Chagas disease. These data bring additional insights that further validate these non-human primates as experimental models for Chagas disease.
authors.affiliation: Grupo Integrado de Pesquisas em Biomarcadores, Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, MG, Brazil.|Southwest National Primates Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States of America.
authors.forename: Danielle Marquete
authors.initials: DM
authors.lastname: Vitelli-Avelar
authors.affiliation: Grupo Integrado de Pesquisas em Biomarcadores, Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, MG, Brazil.|Southwest National Primates Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States of America.|Centro Universitário Newton Paiva, Belo Horizonte, MG, Brazil.|Faculdade de Minas-FAMINAS-BH, Belo Horizonte, MG, Brazil.
authors.forename: Renato
authors.initials: R
authors.lastname: Sathler-Avelar
authors.affiliation: Grupo Integrado de Pesquisas em Biomarcadores, Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, MG, Brazil.|Centro Universitário Newton Paiva, Belo Horizonte, MG, Brazil.|Faculdade de Minas-FAMINAS-BH, Belo Horizonte, MG, Brazil.
authors.forename: Armanda Moreira
authors.initials: AM
authors.lastname: Mattoso-Barbosa
authors.affiliation: Universidad de La Serena, La Serena, Chile.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gouin
authors.affiliation: Grupo Integrado de Pesquisas em Biomarcadores, Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, MG, Brazil.|Centro Universitário Newton Paiva, Belo Horizonte, MG, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Perdigão-de-Oliveira
authors.affiliation: Grupo Integrado de Pesquisas em Biomarcadores, Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, MG, Brazil.|Centro Universitário Newton Paiva, Belo Horizonte, MG, Brazil.
authors.forename: Leydiane
authors.initials: L
authors.lastname: Valério-Dos-Reis
authors.affiliation: Centro Universitário Newton Paiva, Belo Horizonte, MG, Brazil.
authors.forename: Ronaldo Peres
authors.initials: RP
authors.lastname: Costa
authors.affiliation: Grupo Integrado de Pesquisas em Biomarcadores, Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, MG, Brazil.|Departamento de Propedêutica Complementar, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Silvana Maria
authors.initials: SM
authors.lastname: Elói-Santos
authors.affiliation: Laboratório de Bioinformática e Análise Molecular, Instituto de Genética e Bioquímica Universidade Federal de Uberlândia, Campus Patos de Minas, Patos de Minas, MG, Brazil.
authors.forename: Matheus de Souza
authors.initials: MS
authors.lastname: Gomes
authors.affiliation: Laboratório de Bioinformática e Análise Molecular, Faculdade de Ciência da Computação, Universidade Federal de Uberlândia, Campus Patos de Minas, Patos de Minas, MG, Brazil.
authors.forename: Laurence Rodrigues do
authors.initials: LR
authors.lastname: Amaral
authors.affiliation: Grupo Integrado de Pesquisas em Biomarcadores, Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, MG, Brazil.
authors.forename: Andréa
authors.initials: A
authors.lastname: Teixeira-Carvalho
authors.affiliation: Grupo Integrado de Pesquisas em Biomarcadores, Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, MG, Brazil.
authors.forename: Olindo Assis
authors.initials: OA
authors.lastname: Martins-Filho
authors.affiliation: Southwest National Primates Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States of America.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Dick
authors.affiliation: Southwest National Primates Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States of America.
authors.forename: Gene B
authors.initials: GB
authors.lastname: Hubbard
authors.affiliation: Southwest National Primates Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States of America.|South Texas Diabetes and Obesity Institute, School of Medicine, the University of Texas Rio Grande Valley, Brownsville/Harlingen/Edinburg, TX, United States of America.
authors.forename: Jane F
authors.initials: JF
authors.lastname: VandeBerg
authors.affiliation: Southwest National Primates Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States of America.|South Texas Diabetes and Obesity Institute, School of Medicine, the University of Texas Rio Grande Valley, Brownsville/Harlingen/Edinburg, TX, United States of America.
authors.forename: John L
authors.initials: JL
authors.lastname: VandeBerg
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D014355:Chagas Disease / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008252:Macaca fascicularis; D008297:Male; D014349:Trypanosoma cruzi / Q000276:immunology / Q000502:physiology*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D016753:Interleukin-10; D007371:Interferon-gamma