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Nature2024; 632(8025); 614-621; doi: 10.1038/s41586-024-07740-2

Shifts in receptors during submergence of an encephalitic arbovirus.

Abstract: Western equine encephalitis virus (WEEV) is an arthropod-borne virus (arbovirus) that frequently caused major outbreaks of encephalitis in humans and horses in the early twentieth century, but the frequency of outbreaks has since decreased markedly, and strains of this alphavirus isolated in the past two decades are less virulent in mammals than strains isolated in the 1930s and 1940s. The basis for this phenotypic change in WEEV strains and coincident decrease in epizootic activity (known as viral submergence) is unclear, as is the possibility of re-emergence of highly virulent strains. Here we identify protocadherin 10 (PCDH10) as a cellular receptor for WEEV. We show that multiple highly virulent ancestral WEEV strains isolated in the 1930s and 1940s, in addition to binding human PCDH10, could also bind very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2), which are recognized by another encephalitic alphavirus as receptors. However, whereas most of the WEEV strains that we examined bind to PCDH10, a contemporary strain has lost the ability to recognize mammalian PCDH10 while retaining the ability to bind avian receptors, suggesting WEEV adaptation to a main reservoir host during enzootic circulation. PCDH10 supports WEEV E2-E1 glycoprotein-mediated infection of primary mouse cortical neurons, and administration of a soluble form of PCDH10 protects mice from lethal WEEV challenge. Our results have implications for the development of medical countermeasures and for risk assessment for re-emerging WEEV strains.
© 2024. The Author(s).
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Publication Date: 2024-07-24 PubMed ID: 39048821PubMed Central: PMC11324528DOI: 10.1038/s41586-024-07740-2Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Overview

  • This research identifies a cellular receptor called protocadherin 10 (PCDH10) for Western equine encephalitis virus (WEEV) and explores changes in receptor usage by different WEEV strains over time, which may explain shifts in the virus’s virulence and host specificity.

Background and Motivation

  • Western equine encephalitis virus (WEEV) is an alphavirus transmitted by arthropods that historically caused significant encephalitic outbreaks in humans and horses.
  • Outbreaks were common in the early 20th century, but since then have decreased significantly in frequency and severity.
  • Modern WEEV strains isolated in recent decades show reduced virulence compared to ancestral strains from the 1930s and 1940s.
  • This phenomenon, known as viral submergence, involves changes in the virus phenotype and reduced epidemic potential, but the underlying molecular mechanisms were unclear.
  • Understanding receptor usage changes could clarify how the virus has adapted to different hosts and lost virulence, and inform risk of re-emergence of dangerous strains.

Identification of Virus Receptors

  • The researchers identified protocadherin 10 (PCDH10), a cellular protein, as a receptor that WEEV uses to infect mammalian cells.
  • They tested multiple highly virulent ancestral WEEV strains from the 1930s and 1940s and found these strains could bind not only PCDH10 but also two other receptors: very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2).
  • VLDLR and ApoER2 are receptors already known to be used by another encephalitic alphavirus, indicating some shared receptor mechanisms among related viruses.

Changes in Receptor Usage Over Time

  • Most modern WEEV strains retain the ability to bind PCDH10, but a contemporary strain examined lost the ability to bind mammalian PCDH10.
  • This contemporary strain maintained the ability to bind avian receptors, suggesting a host adaptation shift favoring enzootic circulation in bird reservoir hosts rather than mammals.
  • This shift in receptor binding preference may contribute to the observed decrease in virulence and outbreak severity in recent decades.

Functional Role of PCDH10 and Implications

  • PCDH10 was shown to facilitate WEEV glycoprotein-mediated infection in primary mouse cortical neurons, linking receptor usage to neurological infection potential.
  • Provision of soluble PCDH10 protein protected mice from lethal WEEV challenge, implying therapeutic potential by blocking virus entry.
  • This discovery offers a target for developing medical countermeasures, such as receptor blockers or vaccines designed to interfere with receptor binding.
  • Understanding receptor usage patterns also aids risk assessment for re-emerging strains that could regain virulence or switch host specificity.

Summary

  • The study elucidates a key molecular factor, PCDH10, involved in how WEEV infects mammalian hosts and documents shifts in receptor usage during viral evolution.
  • These findings enhance understanding of viral submergence and host adaptation, helping explain the decreased outbreak severity of WEEV over time.
  • The work provides important insights for future surveillance and development of protective treatments against WEEV and related encephalitic alphaviruses.

Cite This Article

APA
Li W, Plante JA, Lin C, Basu H, Plung JS, Fan X, Boeckers JM, Oros J, Buck TK, Anekal PV, Hanson WA, Varnum H, Wells A, Mann CJ, Tjang LV, Yang P, Reyna RA, Mitchell BM, Shinde DP, Walker JL, Choi SY, Brusic V, Llopis PM, Weaver SC, Umemori H, Chiu IM, Plante KS, Abraham J. (2024). Shifts in receptors during submergence of an encephalitic arbovirus. Nature, 632(8025), 614-621. https://doi.org/10.1038/s41586-024-07740-2

Publication

Nature
ISSN: 1476-4687
NlmUniqueID: 0410462
Country: England
Language: English
Volume: 632
Issue: 8025
Pages: 614-621

Researcher Affiliations

Li, Wanyu
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Plante, Jessica A
  • World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA.
  • Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
  • Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
Lin, ChieYu
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Basu, Himanish
  • Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Plung, Jesse S
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Fan, Xiaoyi
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Boeckers, Joshua M
  • Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Oros, Jessica
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Buck, Tierra K
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Anekal, Praju V
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • MicRoN Core, Harvard Medical School, Boston, MA, USA.
Hanson, Wesley A
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Varnum, Haley
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Wells, Adrienne
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • MicRoN Core, Harvard Medical School, Boston, MA, USA.
Mann, Colin J
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Tjang, Laurentia V
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Yang, Pan
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Reyna, Rachel A
  • World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA.
  • Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
  • Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
Mitchell, Brooke M
  • World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA.
  • Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
  • Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
Shinde, Divya P
  • World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA.
  • Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
  • Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
Walker, Jordyn L
  • World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA.
  • Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
  • Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
Choi, So Yoen
  • Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Brusic, Vesna
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Llopis, Paula Montero
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • MicRoN Core, Harvard Medical School, Boston, MA, USA.
Weaver, Scott C
  • World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA.
  • Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
  • Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
Umemori, Hisashi
  • Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Chiu, Isaac M
  • Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Plante, Kenneth S
  • World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA.
  • Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
  • Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
Abraham, Jonathan
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. jonathan_abraham@hms.harvard.edu.
  • Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, USA. jonathan_abraham@hms.harvard.edu.
  • Center for Integrated Solutions in Infectious Diseases, Broad Institute of Harvard and MIT, Cambridge, MA, USA. jonathan_abraham@hms.harvard.edu.

MeSH Terms

  • Animals
  • Female
  • Humans
  • Male
  • Mice
  • Birds / metabolism
  • Birds / virology
  • Communicable Diseases, Emerging / epidemiology
  • Communicable Diseases, Emerging / virology
  • Encephalitis Virus, Western Equine / classification
  • Encephalitis Virus, Western Equine / metabolism
  • Encephalitis Virus, Western Equine / pathogenicity
  • Encephalomyelitis, Equine / epidemiology
  • Encephalomyelitis, Equine / virology
  • Host Specificity
  • LDL-Receptor Related Proteins / metabolism
  • Neurons / metabolism
  • Neurons / virology
  • Phenotype
  • Protocadherins / metabolism
  • Receptors, LDL / metabolism
  • Receptors, LDL / genetics
  • Receptors, Virus / metabolism
  • Viral Envelope Proteins / metabolism
  • Viral Zoonoses / epidemiology
  • Viral Zoonoses / virology

Grant Funding

  • R01 MH125162 / NIMH NIH HHS
  • R01 AI168005 / NIAID NIH HHS
  • T32 AG000222 / NIA NIH HHS
  • T32 AI007245 / NIAID NIH HHS
  • T32 CA009216 / NCI NIH HHS
  • T32 GM144273 / NIGMS NIH HHS
  • R01 AI182377 / NIAID NIH HHS
  • U01 AI151801 / NIAID NIH HHS
  • R24 AI120942 / NIAID NIH HHS
  • T32 GM008313 / NIGMS NIH HHS

Conflict of Interest Statement

The authors declare no competing interests.

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