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VLDLR and ApoER2 are receptors for multiple alphaviruses

Author

Listed:
  • 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
    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
    University of Texas Medical Branch
    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
    MicRoN Core, Harvard Medical School)

  • Scott C. Weaver

    (University of Texas Medical Branch
    University of Texas Medical Branch
    University of Texas Medical Branch)

  • Jonathan Abraham

    (Blavatnik Institute, Harvard Medical School
    Brigham and Women’s Hospital
    Broad Institute of Harvard and MIT)

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.

Suggested Citation

  • 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. Ah, 2022. "VLDLR and ApoER2 are receptors for multiple alphaviruses," Nature, Nature, vol. 602(7897), pages 475-480, February.
  • Handle: RePEc:nat:nature:v:602:y:2022:i:7897:d:10.1038_s41586-021-04326-0
    DOI: 10.1038/s41586-021-04326-0
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    Citations

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    Cited by:

    1. Xiaofeng Zhai & Xiaoling Li & Michael Veit & Ningning Wang & Yu Wang & Andres Merits & Zhiwen Jiang & Yan Qin & Xiaoguang Zhang & Kaili Qi & Houqi Jiao & Wan-Ting He & Ye Chen & Yang Mao & Shuo Su, 2024. "LDLR is used as a cell entry receptor by multiple alphaviruses," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Duanfang Cao & Bingting Ma & Ziyi Cao & Xiaoyu Xu & Xinzheng Zhang & Ye Xiang, 2024. "The receptor VLDLR binds Eastern Equine Encephalitis virus through multiple distinct modes," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Maureen Ritter & Lola Canus & Anupriya Gautam & Thomas Vallet & Li Zhong & Alexandre Lalande & Bertrand Boson & Apoorv Gandhi & Sergueï Bodoirat & Julien Burlaud-Gaillard & Natalia Freitas & Philippe , 2024. "The low-density lipoprotein receptor and apolipoprotein E associated with CCHFV particles mediate CCHFV entry into cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Hongming Ma & Lucas J. Adams & Saravanan Raju & Alan Sariol & Natasha M. Kafai & Hana Janova & William B. Klimstra & Daved H. Fremont & Michael S. Diamond, 2024. "The low-density lipoprotein receptor promotes infection of multiple encephalitic alphaviruses," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Ningning Wang & Andres Merits & Michael Veit & Laura Sandra Lello & Shuhan Kong & Houqi Jiao & Jie Chen & Yu Wang & Georgi Dobrikov & Félix A. Rey & Shuo Su, 2024. "LDL receptor in alphavirus entry: structural analysis and implications for antiviral therapy," Nature Communications, Nature, vol. 15(1), pages 1-7, December.
    6. Pan Yang & Wanyu Li & Xiaoyi Fan & Junhua Pan & Colin J. Mann & Haley Varnum & Lars E. Clark & Sarah A. Clark & Adrian Coscia & Himanish Basu & Katherine Nabel Smith & Vesna Brusic & Jonathan Abraham, 2024. "Structural basis for VLDLR recognition by eastern equine encephalitis virus," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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