VLDLR and ApoER2 are receptors for multiple alphaviruses

Lars E. Clark, Sarah A. Clark, ChieYu Lin, Jianying Liu, Adrian Coscia, Katherine G. Nabel, Pan Yang, Dylan V. Neel, Hyo Lee, Vesna Brusic, Iryna Stryapunina, Kenneth S. Plante, Asim A. Ahmed, Flaminia Catteruccia, Tracy L. Young-Pearse, Isaac M. Chiu, Paula Montero Llopis, Scott C. Weaver and Jonathan Abraham ()
Additional contact information
Lars E. Clark: Blavatnik Institute, Harvard Medical School
Sarah A. Clark: Blavatnik Institute, Harvard Medical School
ChieYu Lin: Blavatnik Institute, Harvard Medical School
Jianying Liu: University of Texas Medical Branch
Adrian Coscia: Blavatnik Institute, Harvard Medical School
Katherine G. Nabel: Blavatnik Institute, Harvard Medical School
Pan Yang: Blavatnik Institute, Harvard Medical School
Dylan V. Neel: Blavatnik Institute, Harvard Medical School
Hyo Lee: Brigham & Women’s Hospital, Harvard Medical School
Vesna Brusic: Blavatnik Institute, Harvard Medical School
Iryna Stryapunina: Harvard T.H. Chan School of Public Health
Kenneth S. Plante: University of Texas Medical Branch
Asim A. Ahmed: Boston Children’s Hospital
Flaminia Catteruccia: Harvard T.H. Chan School of Public Health
Tracy L. Young-Pearse: Brigham & Women’s Hospital, Harvard Medical School
Isaac M. Chiu: Blavatnik Institute, Harvard Medical School
Paula Montero Llopis: Blavatnik Institute, Harvard Medical School
Scott C. Weaver: University of Texas Medical Branch
Jonathan Abraham: Blavatnik Institute, Harvard Medical School

Nature, 2022, vol. 602, issue 7897, 475-480

Abstract: 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 described1–3, 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.

Date: 2022
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DOI: 10.1038/s41586-021-04326-0

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