Profiling an Enhanced IL‐6 Expression Distinguishes Host Susceptibility to Primary and Secondary Infections of the Dengue Virus in an Ex Vivo Whole‐Blood Coculture Model

Dengue virus (DENV) infection can potentially lead to severe dengue disease due to the risk of antibody‐dependent enhancement. This study reports a comparative analysis of the host cytokine/chemokine response triggered by primary and secondary DENV infections using an artificial ex vivo whole‐blood coculture model to simulate viremia during the acute febrile phase of infection. Using ex vivo primary and secondary DENV infection modes, a dengue‐specific customized multiplex cytokine/chemokine assay was employed. Secondary infection did not exacerbate DENV‐induced hematological and cytopathological changes, such as alterations in complete blood count, intracellular vacuolization, and thrombophagocytosis. However, cytokine/chemokine assay revealed a significant increase in the production of MIP‐1 α , MIP‐1 β , IL‐6, TNF‐ α , and RANTES. Notably, a substantial decrease in NS1 levels indicated the neutralization effect in individuals with prior DENV exposure or secondary infection group, especially in some cases of secondary infection. This was accompanied by pre‐existing anti‐E antibodies, highly associated with IL‐6 overproduction. These findings support the potential strategy of assessing DENV susceptibility using NS1 and IL‐6 using an ex vivo method.