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

ABSTRACT 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 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 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 and requires proximal BCR signaling. Finally, we show that DENV-reactive B cells are productively infected by live DENV, capable of supporting active viral replication and dissemination. 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.