Hypoxia enhances antibody‐dependent dengue virus infection

Abstract

Dengue virus ( DENV ) has been found to replicate in lymphoid organs such as the lymph nodes, spleen, and liver in post‐mortem analysis. These organs are known to have low oxygen levels (~0.5–4.5% O 2 ) due to the vascular anatomy. However, how physiologically low levels of oxygen affect DENV infection via hypoxia‐induced changes in the immune response remains unknown. Here, we show that monocytes adapted to 3% O 2 show greater susceptibility to antibody‐dependent enhancement of DENV infection. Low oxygen level induces HIF 1α‐dependent upregulation of fragment crystallizable gamma receptor IIA (Fcγ RIIA ) as well as HIF 1α‐independent alterations in membrane ether lipid concentrations. The increased Fcγ RIIA expression operates synergistically with altered membrane composition, possibly through increase membrane fluidity, to increase uptake of DENV immune complexes for enhanced infection. Our findings thus indicate that the increased viral burden associated with secondary DENV infection is antibody‐dependent but hypoxia‐induced and suggest a role for targeting hypoxia‐induced factors for anti‐dengue therapy. image Physiologically low oxygen levels in lymphoid organs induce HIF 1α‐dependent upregulation of Fcγ RIIA and HIF 1α‐independent enrichment in membrane ether PE lipids to enhance antibody‐dependent dengue virus (DENV) infection in monocytic cells. Active DENV replication occurs in lymph nodes, which have low tissue oxygen tensions (˜3% O 2 ). Low oxygen levels stabilize HIF1α that upregulates FcγRIIA expression. Low oxygen levels also enrich ether PE lipids in cellular membranes through HIF 1α‐independent mechanisms. Alterations in Fcγ RIIA expression and membrane ether lipid composition collectively result in increased susceptibility to antibody‐dependent dengue infection.