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- W4313373379 abstract "Abstract Dengue virus (DENV) is a medically important, mosquito-borne flavivirus that infects up to 390 million people annually. A signature of severe DENV infection is vascular leak, which can lead to shock and organ failure. We and others have shown that secreted DENV non-structural protein 1 (NS1) triggers endothelial cell (EC) hyperpermeability and vascular leak. Antibodies (Abs) targeting NS1 prevent NS1-induced EC hyperpermeability in vitro and are protective against lethal DENV challenge, as shown by vaccination of mice against NS1 and passive transfer of α-NS1 polyclonal serum. How α-NS1 Abs protect against pathogenesis, however, remains obscure. Here we characterize possible mechanisms behind the protective ability of an NS1-specific monoclonal Ab, 2B7. We show that 2B7 abrogates NS1 binding to ECs and EC hyperpermeability in vitro and inhibits vascular leak and mortality in vivo. Guided by crystal structures of NS1 complexed to a 2B7 Fab fragment, we mutated the amino acids on NS1 that comprise the NS1:2B7 interface. Intriguingly, while these contact sites were critical for the interaction between 2B7 and NS1, they were dispensable for NS1:EC binding. The structures and mutagenesis results suggest that 2B7 abrogates NS1 binding indirectly by sterically hindering the binding domain on NS1 from interacting with ECs. The mutagenesis also identified a key residue on NS1 that is necessary for inducing EC hyperpermeability without affecting NS1:EC binding, suggesting that 2B7 may also block an additional step in NS1 pathogenesis. This work provides mechanistic insight into the blockade of DENV NS1-mediated pathogenesis by α-NS1 Abs and identifies critical domains that serve as targets for drugs and vaccine-induced α-NS1 Ab responses." @default.
- W4313373379 created "2023-01-06" @default.
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- W4313373379 date "2020-05-01" @default.
- W4313373379 modified "2023-10-16" @default.
- W4313373379 title "Characterization of a protective antibody against dengue virus non-structural protein 1 (NS1) reveals critical domains required for NS1-triggered pathogenesis" @default.
- W4313373379 doi "https://doi.org/10.4049/jimmunol.204.supp.167.23" @default.
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