VLDLR and ApoER2 are receptors for multiple alphaviruses

Nature. 2022 Feb;602(7897):475-480. doi: 10.1038/s41586-021-04326-0.

Lars E Clark ^# ¹, Sarah A Clark ^# ¹, ChieYu Lin ^# ¹, Jianying Liu ^# ² ³, Adrian Coscia ¹, Katherine G Nabel ¹, Pan Yang ¹, Dylan V Neel ⁴, Hyo Lee ⁵, Vesna Brusic ¹, Iryna Stryapunina ⁶, Kenneth S Plante ² ³ ⁷, Asim A Ahmed ⁸, Flaminia Catteruccia ⁶, Tracy L Young-Pearse ⁵, Isaac M Chiu ⁴, Paula Montero Llopis ¹ ⁹, Scott C Weaver ² ³ ⁷, Jonathan Abraham ¹⁰ ¹¹ ¹²

Affiliations

1 Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
2 Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
3 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
4 Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
5 Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.
6 Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
7 World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA.
8 Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA.
9 MicRoN Core, Harvard Medical School, Boston, MA, USA.
10 Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. jonathan_abraham@hms.harvard.edu.
11 Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, USA. jonathan_abraham@hms.harvard.edu.
12 Broad Institute of Harvard and MIT, Cambridge, MA, USA. jonathan_abraham@hms.harvard.edu.
# Contributed equally.

PMID: 34929721 DOI: 10.1038/s41586-021-04326-0

Abstract

Alphaviruses, like many Other arthropod-borne viruses, infect vertebrate species and insect vectors separated by hundreds of millions of years of evolutionary history. Entry into evolutionarily divergent host cells can be accomplished by recognition of different cellular receptors in different species, or by binding to receptors that are highly conserved across species. Although multiple alphavirus receptors have been described^1-3, most are not shared among vertebrate and invertebrate hosts. Here we identify the very low-density lipoprotein receptor (VLDLR) as a receptor for the prototypic alphavirus Semliki forest virus. We show that the E2 and E1 glycoproteins (E2-E1) of Semliki forest virus, eastern equine encephalitis virus and Sindbis virus interact with the ligand-binding domains (LBDs) of VLDLR and Apolipoprotein E receptor 2 (ApoER2), two closely related receptors. Ectopic expression of either protein facilitates cellular attachment, and internalization of virus-like particles, a VLDLR LBD-Fc fusion protein or a ligand-binding antagonist block Semliki forest virus E2-E1-mediated Infection of human and mouse neurons in culture. The administration of a VLDLR LBD-Fc fusion protein has protective activity against rapidly fatal Semliki forest virus Infection in mouse neonates. We further show that invertebrate receptor orthologues from mosquitoes and worms can serve as functional alphavirus receptors. We propose that the ability of some alphaviruses to infect a wide range of hosts is a result of their engagement of evolutionarily conserved lipoprotein receptors and contributes to their pathogenesis.

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