Felipe Gomes Naveca, Gemilson Soares Pontes, Aileen Yu-hen Chang, George Allan Villarouco da Silva, Valdinete Alves do Nascimento, Dana Cristina da Silva Monteiro, Marineide Souza da Silva, Lígia Fernandes Abdalla, João Hugo Abdalla Santos, Tatiana Amaral Pires de Almeida, Matilde del Carmen Contreras Mejía, Tirza Gabrielle Ramos de Mesquita, Helia Valeria de Souza Encarnação, Matheus de Souza Gomes, Laurence Rodrigues Amaral, Ana Carolina Campi-Azevedo, Jordana Graziela Coelho-dos-Reis, Lis Ribeiro do Vale Antonelli, Andréa Teixeira-Carvalho, Olindo Assis Martins-Filho, Rajendranath Ramasawmy

Infection with Zika virus (ZIKV) manifests in a broad spectrum of disease ranging from mild illness to severe neurological complications and little is known about Zika immunopathogenesis. To define the immunologic biomarkers that correlate with acute 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 symptom onset using microbeads multiplex immunoassay; comparison to 100 age-matched controls was performed for statistical analysis and data mining. 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 the acute infection. Interestingly, the inflammatory cytokines IL-1β, IL-13, IL-17, TNF-α, and IFN-γ; chemokines CXCL8, CCL2, CCL5; and the growth factor G-CSF, displayed a bimodal distribution accompanying viremia. While this is the first manuscript to document bimodal distributions of viremia in ZIKV infection, this has been documented in other viral infections, with a primary viremia peak during mild systemic disease and a secondary peak associated with distribution of the virus to organs and tissues. Biomarker network analysis demonstrated distinct dynamics in concurrence with the bimodal viremia profiles at different time points during ZIKV infection. Such a robust cytokine and chemokine response has been associated with blood-brain barrier permeability and neuroinvasiveness in other flaviviral infections. High-dimensional data analysis further identified CXCL10, a chemokine involved in foetal neuron apoptosis and Guillain-Barré syndrome, as the most promising biomarker of acute ZIKV infection for potential clinical application.