TLR2/MyD88 pathway-dependent regulation of dendritic cells by dengue virus promotes antibody-dependent enhancement via Th2-biased immunity

Possible risk mediators in primary dengue virus (DenV) infection that favor secondary DenV infection to life-threatening dengue hemorrhagic fever (DHF) and shock syndrome (DSS) via antibody-dependent enhancement (ADE) have not yet been described. Here, DenV infection enhanced the expression of inflammatory mediators and activation molecules in dendritic cells (DCs) through TLR2/MyD88 pathway. TLR2 appeared to facilitate DenV infection in DCs that were less permissive than macrophages for viral replication. In experiments using separate evaluations of DenV-infected and uninfected bystander DCs, infected DCs showed impaired maturation accompanied with TLR2-dependent production of inflammatory cytokines, by which uninfected bystander DCs showed increased expression of co-stimulatory molecules. Differential phosphorylation of MAPK and STAT3 was also detected between DenV-infected and uninfected DCs. Furthermore, DenV infection stimulated Th2-polarized humoral and cellular immunity against foreign and DenV Ag via TLR2/MyD88 pathway, and DenV-infected DCs were revealed to facilitate Th2-biased immune responses in TLR2-dependent manner. TLR2/MyD88-mediated Th2-biased Ab responses to primary DenV infection increased the infectivity of secondary homotypic or heterotypic DenV via ADE. Collectively, these results indicate that TLR2/MyD88 pathway in DC-priming receptors can drive Th2-biased immune responses during primary DenV infection, which could favor secondary DenV infection to DHF/DSS via ADE.