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The low-density lipoprotein receptor promotes infection of multiple encephalitic alphaviruses

Author

Listed:
  • Hongming Ma

    (Washington University School of Medicine)

  • Lucas J. Adams

    (Washington University School of Medicine)

  • Saravanan Raju

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Alan Sariol

    (Washington University School of Medicine)

  • Natasha M. Kafai

    (Washington University School of Medicine)

  • Hana Janova

    (Washington University School of Medicine
    Washington University School of Medicine)

  • William B. Klimstra

    (The University of Pittsburgh)

  • Daved H. Fremont

    (Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine)

  • Michael S. Diamond

    (Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine)

Abstract

Members of the low-density lipoprotein receptor (LDLR) family, including LDLRAD3, VLDLR, and ApoER2, were recently described as entry factors for different alphaviruses. However, based on studies with gene edited cells and knockout mice, blockade or abrogation of these receptors does not fully inhibit alphavirus infection, indicating the existence of additional uncharacterized entry factors. Here, we perform a CRISPR-Cas9 genome-wide loss-of-function screen in mouse neuronal cells with a chimeric alphavirus expressing the Eastern equine encephalitis virus (EEEV) structural proteins and identify LDLR as a candidate receptor. Expression of LDLR on the surface of neuronal or non-neuronal cells facilitates binding and infection of EEEV, Western equine encephalitis virus, and Semliki Forest virus. Domain mapping and binding studies reveal a low-affinity interaction with LA domain 3 (LA3) that can be enhanced by concatenation of LA3 repeats. Soluble decoy proteins with multiple LA3 repeats inhibit EEEV infection in cell culture and in mice. Our results establish LDLR as a low-affinity receptor for multiple alphaviruses and highlight a possible path for developing inhibitors that could mitigate infection and disease.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44624-x
    DOI: 10.1038/s41467-023-44624-x
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    References listed on IDEAS

    as
    1. Hongming Ma & Arthur S. Kim & Natasha M. Kafai & James T. Earnest & Aadit P. Shah & James Brett Case & Katherine Basore & Theron C. Gilliland & Chengqun Sun & Christopher A. Nelson & Larissa B. Thackr, 2020. "LDLRAD3 is a receptor for Venezuelan equine encephalitis virus," Nature, Nature, vol. 588(7837), pages 308-314, December.
    2. Deborah Fass & Stephen Blacklow & Peter S. Kim & James M. Berger, 1997. "Molecular basis of familial hypercholesterolaemia from structure of LDL receptor module," Nature, Nature, vol. 388(6643), pages 691-693, August.
    3. Rong Zhang & Arthur S. Kim & Julie M. Fox & Sharmila Nair & Katherine Basore & William B. Klimstra & Rebecca Rimkunas & Rachel H. Fong & Hueylie Lin & Subhajit Poddar & James E. Crowe & Benjamin J. Do, 2018. "Mxra8 is a receptor for multiple arthritogenic alphaviruses," Nature, Nature, vol. 557(7706), pages 570-574, May.
    4. Bingting Ma & Cuiqing Huang & Jun Ma & Ye Xiang & Xinzheng Zhang, 2021. "Structure of Venezuelan equine encephalitis virus with its receptor LDLRAD3," Nature, Nature, vol. 598(7882), pages 677-681, October.
    5. Jovan Nikolic & Laura Belot & Hélène Raux & Pierre Legrand & Yves Gaudin & Aurélie Albertini, 2018. "Structural basis for the recognition of LDL-receptor family members by VSV glycoprotein," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    6. Katherine Basore & Hongming Ma & Natasha M. Kafai & Samantha Mackin & Arthur S. Kim & Christopher A. Nelson & Michael S. Diamond & Daved H. Fremont, 2021. "Structure of Venezuelan equine encephalitis virus in complex with the LDLRAD3 receptor," Nature, Nature, vol. 598(7882), pages 672-676, October.
    7. 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.
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    Cited by:

    1. 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.

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