Shifts in receptors during submergence of an encephalitic arbovirus

Wanyu Li, Jessica A. Plante, ChieYu Lin, Himanish Basu, Jesse S. Plung, Xiaoyi Fan, Joshua M. Boeckers, Jessica Oros, Tierra K. Buck, Praju V. Anekal, Wesley A. Hanson, Haley Varnum, Adrienne Wells, Colin J. Mann, Laurentia V. Tjang, Pan Yang, Rachel A. Reyna, Brooke M. Mitchell, Divya P. Shinde, Jordyn L. Walker, So Yoen Choi, Vesna Brusic, Paula Montero Llopis, Scott C. Weaver, Hisashi Umemori, Isaac M. Chiu, Kenneth S. Plante and Jonathan Abraham ()
Additional contact information
Wanyu Li: Harvard Medical School
Jessica A. Plante: University of Texas Medical Branch
ChieYu Lin: Harvard Medical School
Himanish Basu: Harvard Medical School
Jesse S. Plung: Harvard Medical School
Xiaoyi Fan: Harvard Medical School
Joshua M. Boeckers: Harvard Medical School
Jessica Oros: Harvard Medical School
Tierra K. Buck: Harvard Medical School
Praju V. Anekal: Harvard Medical School
Wesley A. Hanson: Harvard Medical School
Haley Varnum: Harvard Medical School
Adrienne Wells: Harvard Medical School
Colin J. Mann: Harvard Medical School
Laurentia V. Tjang: Harvard Medical School
Pan Yang: Harvard Medical School
Rachel A. Reyna: University of Texas Medical Branch
Brooke M. Mitchell: University of Texas Medical Branch
Divya P. Shinde: University of Texas Medical Branch
Jordyn L. Walker: University of Texas Medical Branch
So Yoen Choi: Harvard Medical School
Vesna Brusic: Harvard Medical School
Paula Montero Llopis: Harvard Medical School
Scott C. Weaver: University of Texas Medical Branch
Hisashi Umemori: Harvard Medical School
Isaac M. Chiu: Harvard Medical School
Kenneth S. Plante: University of Texas Medical Branch
Jonathan Abraham: Harvard Medical School

Nature, 2024, vol. 632, issue 8025, 614-621

Abstract: 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 1940s1–3. The basis for this phenotypic change in WEEV strains and coincident decrease in epizootic activity (known as viral submergence3) 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 receptors4. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07740-2

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