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bioRxiv : the preprint server for biology2025; 2025.01.01.631009; doi: 10.1101/2025.01.01.631009

Molecular basis for shifted receptor recognition by an encephalitic arbovirus.

Abstract: After decades of inactivity throughout the Americas, western equine encephalitis virus (WEEV) recently re-emerged in South America, causing a large-scale outbreak in humans and horses. WEEV binds protocadherin 10 (PCDH10) as a receptor; however, nonpathogenic strains no longer bind human or equine PCDH10 but retain the ability to bind avian receptors. Highly virulent WEEV strains can also bind the very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) as alternative receptors. Here, by determining cryo-electron microscopy structures of WEEV strains isolated from 1941-2005 bound to mammalian receptors, we identify polymorphisms in the WEEV spike protein that explain shifts in receptor dependencies and that can allow nonpathogenic strains to infect primary cortical neurons. We predict the receptor dependencies of additional strains and of a related North American alphavirus. Our findings have implications for outbreak preparedness and enhance understanding of arbovirus neurovirulence through virus receptor binding patterns.
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Publication Date: 2025-01-02 PubMed ID: 39803583PubMed Central: PMC11722376DOI: 10.1101/2025.01.01.631009Google Scholar: Lookup
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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 investigates how different strains of the western equine encephalitis virus (WEEV) recognize and bind to cellular receptors, explaining why some strains are more virulent and capable of infecting humans and horses, while others are not.
  • The study uses detailed structural techniques to identify changes in the virus that influence which receptors it can bind, shedding light on its ability to cause neurological disease and aiding outbreak preparedness.

Background and Significance

  • Western equine encephalitis virus (WEEV) is an arbovirus that had been inactive in the Americas for decades but has recently caused significant outbreaks in South America affecting both humans and horses.
  • Understanding how WEEV interacts with host cell receptors is critical because receptor binding is key to the virus’s ability to infect cells and cause disease.
  • The virus’s spike protein mediates attachment to receptors on host cells; identifying which receptors are involved helps explain differences in strain pathogenicity.
  • Previously, the primary receptor known for WEEV was protocadherin 10 (PCDH10), but nonpathogenic strains lose the ability to bind human or equine PCDH10, indicating a shift in receptor usage may explain changes in infectivity.

Objectives

  • To define structural differences in the spike proteins from multiple WEEV strains isolated between 1941 and 2005.
  • To determine how these structural differences affect the virus’s ability to bind to various mammalian receptors, including PCDH10, very low-density lipoprotein receptor (VLDLR), and apolipoprotein E receptor 2 (ApoER2).
  • To understand how changes in receptor binding relate to the virus’s virulence, neurotropism (preference for nervous system tissue), and ability to infect certain host species.

Methods

  • Applied cryo-electron microscopy (cryo-EM) to determine high-resolution 3D structures of the virus spike protein in complex with mammalian receptors.
  • Analyzed polymorphisms—genetic variations—in the spike proteins of different WEEV strains to identify how they alter receptor specificity and binding.
  • Performed comparative structural analyses between pathogenic and nonpathogenic strains to pinpoint molecular determinants of receptor affinity shifts.
  • Used these structural insights to predict receptor usage for other strains, including a related North American alphavirus, potentially extending findings beyond WEEV.

Key Findings

  • Identified specific amino acid polymorphisms in the WEEV spike protein that explain shifts from binding PCDH10 to alternative receptors such as VLDLR and ApoER2.
  • Demonstrated that nonpathogenic strains retain binding to avian receptors but lose the ability to bind mammalian PCDH10, correlating with reduced virulence in humans and horses.
  • Established that highly virulent WEEV strains can utilize multiple receptors, which may facilitate infection of a broader range of host cells, including primary cortical neurons involved in neurological disease.
  • Showed that structural variations can enable nonpathogenic strains to gain the ability to infect neuronal cells, which may influence outbreak severity and neurological outcomes.
  • Predicted receptor dependencies in additional WEEV strains and a related alphavirus, offering insight into virus evolution and host range expansion.

Implications and Importance

  • Enhanced understanding of how receptor binding patterns influence arbovirus neurovirulence, which is vital for predicting and managing future outbreaks.
  • Identification of alternative receptors opens potential avenues for therapeutic intervention or vaccine design targeting receptor-virus interactions.
  • Prediction of receptor usage across related strains informs surveillance efforts by indicating which virus variants may pose greater risk to humans and animals.
  • Improved mechanistic insight into virus-host interactions contributes to broader knowledge in virology, receptor biology, and neuroinfectious disease research.
  • Informs public health strategies to monitor viral evolution and emergent pathogenic strains capable of crossing species barriers and causing encephalitic disease.

Cite This Article

APA
Fan X, Li W, Oros J, Plung JS, Plante JA, Basu H, Nagappan-Chettiar S, Boeckers JM, Tjang LV, Mann CJ, Brusic V, Buck TK, Varnum H, Yang P, Malcolm LM, Choi SY, de Souza WM, Chiu IM, Umemori H, Weaver SC, Plante KS, Abraham J. (2025). Molecular basis for shifted receptor recognition by an encephalitic arbovirus. bioRxiv, 2025.01.01.631009. https://doi.org/10.1101/2025.01.01.631009

Publication

bioRxiv : the preprint server for biology
ISSN: 2692-8205
NlmUniqueID: 101680187
Country: United States
Language: English
PII: 2025.01.01.631009

Researcher Affiliations

Fan, Xiaoyi
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Li, Wanyu
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Oros, Jessica
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Plung, Jesse S
  • 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.
Basu, Himanish
  • Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Nagappan-Chettiar, Sivapratha
  • Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, 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.
Tjang, Laurentia V
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Mann, Colin J
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Brusic, Vesna
  • 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.
Varnum, Haley
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Yang, Pan
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Malcolm, Linzy M
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Choi, So Yoen
  • Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
de Souza, William M
  • Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, KY, USA.
Chiu, Isaac M
  • Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Umemori, Hisashi
  • Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, 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.
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.
  • Department of Medicine, Division of Infectious Diseases, Brigham & Women's Hospital, Boston, MA, USA.
  • Center for Integrated Solutions in Infectious Diseases, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Howard Hughes Medical Institute, Boston, MA, USA.

Grant Funding

  • R01 MH125162 / NIMH NIH HHS
  • T32 AG000222 / NIA NIH HHS
  • T32 AI007245 / NIAID NIH HHS
  • T32 GM144273 / NIGMS NIH HHS
  • R24 AI120942 / NIAID NIH HHS
  • R01 AI182377 / NIAID NIH HHS
  • Wellcome Trust

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