Direct Infection of B Cells by Dengue Virus Modulates B Cell Responses in a Cambodian Pediatric Cohort

Abstract

Dengue is an acute viral disease caused by dengue virus (DENV), which is transmitted by Aedes mosquitoes. Symptoms of DENV infection range from inapparent to severe and can be life-threatening. DENV replicates in primary immune cells such as dendritic cells and macrophages, which contribute to the dissemination of the virus. Susceptibility of other immune cells such as B cells to direct infection by DENV and their subsequent response to infection is not well defined. In a cohort of 60 Cambodian children, we showed that B cells are susceptible to DENV infection. Moreover, we show that B cells can support viral replication of laboratory adapted and patient-derived DENV strains. B cells were permissive to DENV infection albeit low titers of infectious virions were released in cell supernatants CD300a, a phosphatidylserine receptor, was identified as a potential attachment factor or receptor for entry of DENV into B cells. In spite of expressing Fcγ-receptors, antibody-mediated enhancement of DENV infection was not observed in B cells in an in vitro model. Direct infection by DENV induced proliferation of B cells in dengue patients in vivo and plasmablast/plasma cell formation in vitro. To summarize, our results show that B cells are susceptible to direct infection by DENV via CD300a and the subsequent B cell responses could contribute to dengue pathogenesis.

Single-cell temporal analysis of natural dengue infection reveals skin-homing lymphocyte expansion one day before defervescence

“…In earlier studies, the down-regulation of ribosomal and translation genes were seen in early DENV infection ( Hanley et al., 2021 ; Roth et al., 2017 ; Waickman et al., 2021 ). Our detailed analysis showed that the translation-related genes were suppressed the most at Day −2 in monocytes and B cells, which are known to be the direct targets of DENV ( Durbin et al., 2008 ; Upasani et al., 2020 ; Zanini et al., 2018 ), and to a lesser extent in non-DENV-targeted populations such as T cells.…”

Antibody fucosylation predicts disease severity in secondary dengue infection

“…As recently demonstrated for other enveloped viruses (15), DENV can modulate IgG1 afucosylation either by eliciting distinctive inflammatory cues to B cells (16) or through direct infection of B cells (17,18). This may modulate Fc fucosylation through inappropriate activation of cellular antiviral responses and/or dysregulated B cell function.…”

Dengue Infection - Recent Advances in Disease Pathogenesis in the Era of COVID-19

“…Recently, B cells has been shown to be directly susceptible to DENV infection. The infected B cells can support low viral replication via CD300a ( 46 ). Interestingly, direct DENV infection of B cell induces their proliferation in vivo and formation of plasmablasts in vitro ( 46 ).…”

“…The infected B cells can support low viral replication via CD300a ( 46 ). Interestingly, direct DENV infection of B cell induces their proliferation in vivo and formation of plasmablasts in vitro ( 46 ). Though ADE is not observed in B cells, the production of massive amounts of non-neutralizing antibodies during secondary infection likely has an association with disease severity ( 46 ).…”

“…Following infection, B cells can be activated by DENV, via direct or indirect modes. Despite relatively poor permissibility, B cells are susceptible to DENV infection via a phosphatidylserine receptor, CD300a that serves as a portal for virus attachment and entry ( 46 ). Coculture of primary B cells with DENV gives rise of substantial amount of IgM release suggesting a heightened level of B cell activation ( 50 ).…”