Structural and functional basis of VLDLR usage by Eastern equine encephalitis virus.

alphavirus cryo-electron microscopy encephalitis mice pathogenesis receptor therapeutic

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
28 Dec 2023
Historique:
received: 01 05 2023
revised: 06 10 2023
accepted: 28 11 2023
medline: 5 1 2024
pubmed: 5 1 2024
entrez: 4 1 2024
Statut: aheadofprint

Résumé

The very-low-density lipoprotein receptor (VLDLR) comprises eight LDLR type A (LA) domains and supports entry of distantly related alphaviruses, including Eastern equine encephalitis virus (EEEV) and Semliki Forest virus (SFV). Here, by resolving multiple cryo-electron microscopy structures of EEEV-VLDLR complexes and performing mutagenesis and functional studies, we show that EEEV uses multiple sites (E1/E2 cleft and E2 A domain) to engage more than one LA domain simultaneously. However, no single LA domain is necessary or sufficient to support efficient EEEV infection. Whereas all EEEV strains show conservation of two VLDLR-binding sites, the EEEV PE-6 strain and a few other EEE complex members feature a single amino acid substitution that enables binding of LA domains to an additional site on the E2 B domain. These structural and functional analyses informed the design of a minimal VLDLR decoy receptor that neutralizes EEEV infection and protects mice from lethal challenge.

Identifiants

DOI: 10.1016/j.cell.2023.11.031 PMID: 38176410
pubmed: 38176410
pii: S0092-8674(23)01318-1
doi: 10.1016/j.cell.2023.11.031
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2023 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests M.S.D. is a consultant or advisor for Inbios, Ocugen, Vir Biotechnology, Topspin Therapeutics, Moderna, Merck, and Immunome. The Diamond laboratory has received funding support from Emergent BioSolutions, Moderna, and Vir Biotechnology. D.H.F. is a founder of Courier Therapeutics and has received funding support from Emergent BioSolutions and Mallinckrodt Pharmaceuticals.

Auteurs

Lucas J Adams (LJ)

Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Saravanan Raju (S)

Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Hongming Ma (H)

Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

Theron Gilliland (T)

The Center for Vaccine Research and Department of Immunology, The University of Pittsburgh, Pittsburgh, PA 15261, USA.

Douglas S Reed (DS)

The Center for Vaccine Research and Department of Immunology, The University of Pittsburgh, Pittsburgh, PA 15261, USA.

William B Klimstra (WB)

The Center for Vaccine Research and Department of Immunology, The University of Pittsburgh, Pittsburgh, PA 15261, USA.

Daved H Fremont (DH)

Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: fremont@wustl.edu.

Michael S Diamond (MS)

Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: mdiamond@wustl.edu.

Classifications MeSH