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The basis for this phenotypic change in WEEV strains and coincident decrease in epizootic activity\u00a0(known as viral submergence<jats:sup>3<\/jats:sup>) 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<jats:sup>4<\/jats:sup>. 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\u2013E1 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.<\/jats:p>","DOI":"10.1038\/s41586-024-07740-2","type":"journal-article","created":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T16:01:55Z","timestamp":1721836915000},"page":"614-621","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Shifts in receptors during submergence of an encephalitic arbovirus"],"prefix":"10.1038","volume":"632","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5964-1545","authenticated-orcid":false,"given":"Wanyu","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4768-7458","authenticated-orcid":false,"given":"Jessica 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