A neutralizing antibody prevents postfusion transition of measles virus fusion protein

• 成果类型: Article
• 署名作者: Zyla, Dawid S.; Della Marca, Roberta; Niemeyer, Gele; Zipursky, Gillian; Stearns, Kyle; Leedale, Cameron; Sobolik, Elizabeth B.; Callaway, Heather M.; Hariharan, Chitra; Peng, Weiwei; Parekh, Diptiben; Marcink, Tara C.; Diaz Avalos, Ruben; Horvat, Branka; Mathieu, Cyrille; Snijder, Joost; Greninger, Alexander L.; Hastie, Kathryn M.; Niewiesk, Stefan; Moscona, Anne; Porotto, Matteo; Saphire, Erica Ollmann
• 署名单位: La Jolla Institute for Immunology; Columbia University; Columbia University; Universita della Campania Vanvitelli; University of Lubeck; University System of Ohio; Ohio State University; University of Washington; University of Washington Seattle; Utrecht University; Utrecht University; Universite Claude Bernard Lyon 1; Ecole Normale Superieure de Lyon (ENS de LYON); Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universite Claude Bernard Lyon 1; Ecole Normale Superieure de Lyon (ENS de LYON); Columbia University; Columbia University; University of California System; University of California San Diego; Montana State University System; Montana State University Bozeman
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12860
• DOI: 10.1126/science.adm8693
• 发表日期: 2024-05-27
• 关键词: UNITED-STATES; paramyxovirus fusion; humoral immunity; membrane-fusion; f protein; vaccine; infection; OUTBREAK; MODEL; cell

摘要

Measles virus (MeV) presents a public health threat that is escalating as vaccine coverage in the generalpopulation declines and as populations of immunocompromised individuals, who cannot be vaccinated,increase. There are no approved therapeutics for MeV. Neutralizing antibodies targeting viral fusionare one potential therapeutic approach but have not yet been structurally characterized or advanced toclinical use. We present cryo-electron microscopy (cryo-EM) structures of prefusion F alone [2.1-angstrom (& Aring;) resolution], F complexed with a fusion-inhibitory peptide (2.3-& Aring; resolution), F complexedwith the neutralizing and protective monoclonal antibody (mAb) 77 (2.6-& Aring; resolution), and an additionalstructure of postfusion F (2.7-& Aring; resolution). In vitro assays and examination of additional EM classesshow that mAb 77 binds prefusion F, arrests F in an intermediate state, and prevents transition to thepostfusion conformation. These structures shed light on antibody-mediated neutralization that involvesarrest of fusion proteins in an intermediate state