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

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-1{beta}, IL-13, IL-17, TNF-, IFN-{gamma}; 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-Barre syndrome, as the most promising biomarker of acute ZIKV infection for a potential clinical application.\n\nAuthor SummaryInfection with Zika virus manifests in a broad spectrum of disease ranging from mild illness to severe neurological complications. This study characterized the levels of circulating cytokines, chemokines and growth factors in Zika-infected patients showing an inflammatory immune response. Specifically, this study identified a chemokine, CXCL10, known to be involved in fetal neuron apoptosis and Guillain-Barre syndrome, as the most promising biomarker to characterize acute Zika virus infection.