B cell receptor dependent infection as a mechanism of immune-mediated enhancement of dengue virus infection and pathogenesis

Four serotypes of dengue virus (DENV1-4) cause 100 million symptomatic dengue cases annually. While the majority of DENV infections resolve without the need for medical intervention, dengue can quickly progress in some patients to potentially fatal dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). The risk factors associated with progressing to severe dengue are complex and incompletely understood. However, the risk of developing severe disease increases significantly in individuals experiencing secondary/heterologous infections. The leading mechanistic explanation for this phenomenon is Antibody-Dependent Enhancement (ADE), wherein DENV-specific IgG antibodies elicited by a prior heterotypic DENV infection opsonize DENV without neutralizing infectivity, facilitating uptake by FcγR-bearing phagocytes such as monocytes and macrophages. However, analysis of samples from individuals experiencing acute DENV infection reveals that B cells are the largest reservoir of infected circulating cells, representing a disconnect in our understanding of immune-mediated DENV tropism. While B cells are known to be phagocytic, their antigen-specific receptors provide an additional means of internalizing extracellular antigens. Our team has recently demonstrated that the expression of a DENV-specific B cell receptor (BCR) renders cells highly susceptible to DENV infection. In addition, we have demonstrated that the frequency of DENV-infectable B cell is influenced by flavivirus immune status, with the frequency of DENV-infectible B cells increasing significant in previously flavivirus-naïve individuals after a primary DENV infection. We posit a new paradigm where cross-reactive non-neutralizing antibodies, when expressed in their transmembrane form as B cell receptors (BCR) on DENV-specific B cells are capable of mediating BCR-dependent enhancement (BDE) DENV infection, replication, and immunopathogenesis. Our long-term goal is to understand how B cells themselves alongside their antibody products can contribute to protection from or susceptibility to DENV infection and disease. Accordingly, our objective with this submission is to define the mechanistic requirements underpinning the process of BDE and to understand how risk of BDE is modulated by DENV infection and/or vaccination.