MEM INST OSWALDO CRUZ, RIO DE JANEIRO, FAST TRACK
PAGES: DOI: 10.1590/0074-02760170542 Full paper
UNDER REVIEW

Analysis of the immunological biomarker profile during acute Zika virus infection reveals the overexpression of CXCL10, a chemokine already linked to neuronal damage

Felipe Gomes Naveca1,2,+, Gemilson Soares Pontes3, Aileen Yu-hen Chang4, George Allan Villarouco da Silva2,7, Valdinete Alves do Nascimento1, Dana Cristina da Silva Monteiro2, Marineide Souza da Silva2, Lígia Fernandes Abdalla2,5, João Hugo Abdalla Santos6, Tatiana Amaral Pires de Almeida1, Matilde del Carmen Contreras Mejía1, Tirza Gabrielle Ramos de Mesquita7, Helia Valeria de Souza Encarnação7, Matheus de Souza Gomes8, Laurence Rodrigues Amaral8, Ana Carolina Campi-Azevedo9, Jordana Graziela Coelho-dos-Reis9, Lis Ribeiro do Vale Antonelli9, Andréa Teixeira-Carvalho9, Olindo Assis Martins-Filho9,+, Rajendranath Ramasawmy7,10

Programa de Pós-Graduação em Biologia da Interação Patógeno-Hospedeiro, Instituto Leônidas e Maria Deane – Fiocruz Amazônia, Manaus, Amazonas, Brazil
2 Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas, Manaus, Amazonas, Brazil
3 Instituto Nacional de Pesquisas da Amazônia, Manaus, Amazonas, Brazil
4 George Washington University, Washington, DC, United States of America
5 Universidade do Estado do Amazonas, Manaus, Amazonas, Brazil
6 Hospital Adventista de Manaus, Manaus, Amazonas, Brazil
7 Fundação de Medicina Tropical – Dr Heitor Vieira Dourado, Manaus, Amazonas, Brazil
8 Universidade Federal de Uberlândia, Patos de Minas, Minas Gerais, Brazil
9 Centro de Pesquisas René Rachou – Fiocruz Minas, Belo Horizonte, Minas Gerais, Brazil
10 Universidade Nilton Lins, Manaus, Amazonas, Brazil

Abstract

Infection with Zika virus (ZIKV) manifests in a broad spectrum of disease ranging from mild illness to severe neurological complications. To define immunologic correlates of ZIKV infection, we characterized the levels of circulating cytokines, chemokines and growth factors in 54 infected patients of both genders, at five different time-points after symptoms onset using microbeads multiplex immunoassay; statistical analysis and data mining compared to 100 age-matched controls. ZIKV-infected patients present a striking systemic inflammatory response with high levels of pro-inflammatory mediators. Despite the strong inflammatory pattern, IL-1Ra and IL-4 are also induced during acute infection. Interestingly, the inflammatory cytokines, IL-1β, IL-13, IL-17, 23 TNF-α, IFN-γ; chemokines, CXCL8, CCL2, CCL5; and the growth factor G-CSF display a bimodal distribution accompanying viremia. While this is the first manuscript to document bimodal distributions of viremia in ZIKV infection, bimodal viremia has been documented in other viral infections with primary viremia peaks during mild systemic disease and a secondary viremia with distribution of the virus to organs and tissues. Moreover, biomarker network analysis demonstrated distinct dynamics in consonance with the bimodal viremia profiles at different time-points during ZIKV infection. Such robust cytokine and chemokine response has been associated with blood-brain barrier permeability and neuroinvasiveness in other flaviviral infections. High-dimensional data analysis further established CXCL10, a chemokine involved in fetal neuron apoptosis and Guillain-Barré syndrome, as the most promising biomarker of acute ZIKV infection for a potential clinical application.

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