title: Callithrix penicillata: a feasible experimental model for dengue virus infection.
abstract: Although the murine models have the feasibility to reproduce some signs of dengue Virus (DENV) infection, the use of isogenic hosts with polarized immune response patterns does not reproduce the particularities of human disease. Our goal was to investigate the kinetics of peripheral blood biomarkers in immunocompetent Callithrix penicillata non-human primates subcutaneously infected with DENV-3. The viral load of infected animals was determinated by quantitative real time PCR. Measurements of DENV-3/IgM were performed, and several parameters were assessed by hemogram: red blood cells count, hemoglobin, hematocrit, white blood cells count, neutrophils, monocytes, lymphocytes, and platelets count. The coagulogram was performed by prothrombin time (PT), and activated partial thromboplastin time (APTT) assays. The renal function was monitored by urea and creatinine, and the liver function by the aspartate (AST), and alanine (ALT) aminotransferases. Also, the level of the cytokines IL-6, TNF-α, IL-2, IFN-γ, IL-4 and IL-5 was quantified during the experimental study. Data analysis was performed considering relevant differences when baseline fold changes were found outside from 0.75 to 1.5 range. Our data demonstrated that infected animals presented relevant signs of dengue disease, including peaks of viremia at 5 days-post-infection (dpi), peaks of anti-DENV-3 IgM at 15 dpi and hemaglutination inhibition assay (HIA) from 15 to at 60 dpi. Despite early monocytosis, slight neutrophilia and lymphocytosis, animals developed persistent leucopenia starting at 4 dpi. Anemia episodes were steady at 3-4 dpi. Patent thrombocytopenia was observed from 1 to 15 dpi with sporadic decrease of APTT. A substantial increase of ALT and AST was observed with higher peak at 4 dpi. Moreover, early increases of TNF-alpha and IFN-gamma besides late increase of IFN-gamma were observed. The analysis of biomarkers network pointed out two relevant strong axes during early stages of dengue fever, a protective axes TNF-alpha/Lymphocytes/Platelets, and a pathological IL-2/IL-6/Viremia/Monocyte/PT bond. Later on, the biomarker network highlighted the interaction IFN-gamma/PLT/DENV-3(IgM;HAI)/PT, and the involvement of type-2 cytokines (IL-4; IL-5). Our findings demonstrated that C. penicillata is a feasible experimental model for dengue virus infection, which could be useful to pathogenesis studies, discovery of novel antiviral drugs as well as to evaluate vaccine candidates against DENV.
authors.affiliation: Instituto Evandro Chagas/SVS/MS, Ananindeua, Pará, Brazil; Núcleo de Medicina Tropical Universidade Federal do Pará, Belém, Pará, Brazil. Electronic address: mileneferreira@iec.pa.gov.br.
authors.forename: Milene Silveira
authors.initials: MS
authors.lastname: Ferreira
authors.affiliation: Centro Nacional de Primatas, Ananindeua, Pará, Brazil. Electronic address: paulo.castro@cenp.org.br.
authors.forename: Paulo Henrique Gomes
authors.initials: PH
authors.lastname: de Castro
authors.affiliation: Centro Nacional de Primatas, Ananindeua, Pará, Brazil. Electronic address: gilmara.silva@cenp.org.br.
authors.forename: Gilmara Abreu
authors.initials: GA
authors.lastname: Silva
authors.affiliation: Instituto Evandro Chagas/SVS/MS, Ananindeua, Pará, Brazil. Electronic address: samircasseb@iec.pa.gov.br.
authors.forename: Samir Mansur Moraes
authors.initials: SM
authors.lastname: Casseb
authors.affiliation: Instituto Evandro Chagas/SVS/MS, Ananindeua, Pará, Brazil. Electronic address: antoniodias@iec.pa.gov.br.
authors.forename: Antônio Gregório
authors.initials: AG
authors.lastname: Dias Júnior
authors.affiliation: Instituto Evandro Chagas/SVS/MS, Ananindeua, Pará, Brazil. Electronic address: suelirodrigues@iec.pa.gov.br.
authors.forename: Sueli Guerreiros
authors.initials: SG
authors.lastname: Rodrigues
authors.affiliation: Instituto Evandro Chagas/SVS/MS, Ananindeua, Pará, Brazil. Electronic address: raimundaazevedo@iec.pa.gov.br.
authors.forename: Raimunda do Socorro da Silva
authors.initials: Rdo S
authors.lastname: Azevedo
authors.affiliation: Laboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz-FIOCRUZ, Belo Horizonte, Brazil. Electronic address: mfernandes@cpqrr.fiocruz.br.
authors.forename: Matheus Fernandes
authors.initials: MF
authors.lastname: Costa e Silva
authors.affiliation: Laboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz-FIOCRUZ, Belo Horizonte, Brazil. Electronic address: daniellezauli@yahoo.com.br.
authors.forename: Danielle Alves Gomes
authors.initials: DA
authors.lastname: Zauli
authors.affiliation: Laboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz-FIOCRUZ, Belo Horizonte, Brazil. Electronic address: sobreira@cpqrr.fiocruz.br.
authors.forename: Márcio Sobreira Silva
authors.initials: MS
authors.lastname: Araújo
authors.affiliation: Laboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz-FIOCRUZ, Belo Horizonte, Brazil. Electronic address: samantha@cpqrr.fiocruz.br.
authors.forename: Samantha Ribeiro
authors.initials: SR
authors.lastname: Béla
authors.affiliation: Laboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz-FIOCRUZ, Belo Horizonte, Brazil. Electronic address: andreat@cpqrr.fiocruz.br.
authors.forename: Andréa
authors.initials: A
authors.lastname: Teixeira-Carvalho
authors.affiliation: Laboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz-FIOCRUZ, Belo Horizonte, Brazil. Electronic address: daniellezauli@cpqrr.fiocruz.br.
authors.forename: Olindo Assis
authors.initials: OA
authors.lastname: Martins-Filho
authors.affiliation: Instituto Evandro Chagas/SVS/MS, Ananindeua, Pará, Brazil; Universidade do Estado do Pará, Belém, Pará, Brazil. Electronic address: pedrovasconcelos@iec.pa.gov.br.
authors.forename: Pedro Fernando da Costa
authors.initials: PF
authors.lastname: Vasconcelos
mesh_terms: D000740:Anemia / Q000209:etiology; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation; D002144:Callithrix / Q000276:immunology*; D002452:Cell Count; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000097:blood; D003715:Dengue / Q000150:complications / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology*; D004195:Disease Models, Animal; D005240:Feasibility Studies; D007075:Immunoglobulin M / Q000097:blood; D007970:Leukopenia / Q000209:etiology; D013921:Thrombocytopenia / Q000209:etiology; D000637:Transaminases / Q000097:blood; D019562:Viral Load
chemical_list: D000914:Antibodies, Viral; D015415:Biomarkers; D016207:Cytokines; D007075:Immunoglobulin M; D003404:Creatinine; D000637:Transaminases
keywords: Dengue virus infection; Experimental model; Immune response; Non-human; Primate