Infection order outweighs the role of CD4+ T cells in tertiary flavivirus infection

This is the authors' abstract. We don't add key points for this paper.

Dengue (DENV) and Zika (ZIKV) are flaviviruses that co-circulate throughout the tropical and subtropical regions. The link between CD4+ T and B cells during immune responses to DENV and ZIKV and their roles in cross-protection during heterologous infection is an active area of research. Here we used CD4+ lymphocyte depletions to dissect the impact of cellular immunity on humoral responses during a tertiary flavivirus infection. We show that CD4+ depletion in DENV-primed animals followed by ZIKV-DENV resulted in delayed viremia followed by increased viral replication in tertiary infections and dysregulated adaptive immune responses compared to ZIKV-primed animals followed by DENV-DENV infections. We show a delay in DENV-specific IgM/IgG antibody titers and neutralization in the DENV-primed CD4-depleted animals but not in ZIKV-primed CD4-depleted animals. This study confirms the critical role of CD4+ cells in viremia control and priming of early and robust neutralizing antibody responses during sequential flavivirus infections. Our results also revealed differential cytokine profiles for both infection sequences regardless of CD4+ status. Our work here suggests that the order of flavivirus exposure affects the outcome of a tertiary infection. Our findings have implications for understanding complex immune responses induced by flaviviruses that co-circulate and develop effective flavivirus vaccines.