Molecular and biophysical requirements for B cell receptor-dependent enhancement of dengue virus infection

Dengue virus (DENV) is the causative agent of dengue, a mosquito-borne disease that represents a significant and growing public health burden around the world. A unique pathophysiological feature of dengue is immune-mediated enhancement, wherein preexisting immunity elicited by a primary infection can enhance the severity of a subsequent infection by a heterologous DENV serotype. A leading mechanistic explanation for this phenomenon is antibody-dependent enhancement (ADE), where sub-neutralizing concentrations of DENV-specific IgG antibodies facilitate the entry of DENV into FcγR-expressing cells. Accordingly, this model posits that phagocytic mononuclear cells are the primary reservoir of DENV. However, multiple independent groups have shown that B cells are the largest reservoir of virally infected cells in circulation during acute dengue, representing a disconnect in our understanding of immune-mediated DENV tropism. In response to this persistent knowledge gap, our team has previously identified a novel mechanism of immune-mediated enhancement we have termed B cell receptor (BCR)-dependent enhancement (BDE) of DENV infection. In this study, we show that DENV infection of DENV-reactive B cells is highly sensitive to BCR/DENV envelope (E) protein interactions. DENV entry into this subset of B cells is dynamin-mediated, requires proximal BCR signaling, and involves localization to late endosomes. Finally, we show that immortalized DENV-reactive B cells are productively infected by live DENV, capable of supporting active viral replication of all four serotypes. We propose that BDE provides an additional layer of pathogen-specific immune-mediated infection risk that complements existing models of ADE and offers additional insight into potential mechanisms of DENV immunopathogenesis.IMPORTANCEThis study provides mechanistic insight into the process of B cell receptor (BCR)-dependent enhancement of dengue virus (DENV) infection. Immune-mediated enhancement of infection is a cornerstone of dengue immunopathogenesis and is most often attributed to antibody-dependent enhancement (ADE). BCR-dependent enhancement of DENV infection is an alternative and complementary mechanism for immune-mediated enhancement that addresses several persistent knowledge gaps in the dengue field and may offer mechanistic insight into why some people progress to severe dengue after infection.