1. Structural basis for antibody inhibition of flavivirus NS1–triggered endothelial dysfunction
- Author
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Biering, Scott B, Akey, David L, Wong, Marcus P, Brown, W Clay, Lo, Nicholas TN, Puerta-Guardo, Henry, Tramontini Gomes de Sousa, Francielle, Wang, Chunling, Konwerski, Jamie R, Espinosa, Diego A, Bockhaus, Nicholas J, Glasner, Dustin R, Li, Jeffrey, Blanc, Sophie F, Juan, Evan Y, Elledge, Stephen J, Mina, Michael J, Beatty, P Robert, Smith, Janet L, and Harris, Eva
- Subjects
Vaccine Related ,Prevention ,Immunization ,Vector-Borne Diseases ,Rare Diseases ,Emerging Infectious Diseases ,Biodefense ,Infectious Diseases ,West Nile Virus ,Aetiology ,2.1 Biological and endogenous factors ,Infection ,Good Health and Well Being ,Animals ,Antibodies ,Monoclonal ,Antibodies ,Neutralizing ,Antibodies ,Viral ,Cross Reactions ,Crystallography ,X-Ray ,Dengue ,Dengue Virus ,Endothelium ,Glycocalyx ,Humans ,Mice ,Protein Conformation ,beta-Strand ,Protein Domains ,Viral Nonstructural Proteins ,West Nile Fever ,West Nile virus ,Zika Virus ,Zika Virus Infection ,General Science & Technology - Abstract
Medically important flaviviruses cause diverse disease pathologies and collectively are responsible for a major global disease burden. A contributing factor to pathogenesis is secreted flavivirus nonstructural protein 1 (NS1). Despite demonstrated protection by NS1-specific antibodies against lethal flavivirus challenge, the structural and mechanistic basis remains unknown. Here, we present three crystal structures of full-length dengue virus NS1 complexed with a flavivirus-cross-reactive, NS1-specific monoclonal antibody, 2B7, at resolutions between 2.89 and 3.96 angstroms. These structures reveal a protective mechanism by which two domains of NS1 are antagonized simultaneously. The NS1 wing domain mediates cell binding, whereas the β-ladder triggers downstream events, both of which are required for dengue, Zika, and West Nile virus NS1-mediated endothelial dysfunction. These observations provide a mechanistic explanation for 2B7 protection against NS1-induced pathology and demonstrate the potential of one antibody to treat infections by multiple flaviviruses.
- Published
- 2021