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 20th century, but outbreak frequency has since decreased drastically, and strains of this alphavirus isolated in the last two decades are less virulent in mammals than strains isolated in the 1930s–40s. The basis for this phenotypic change in WEEV strains and coincident decrease in epizootic activity (“viral submergence") is unclear, as is the possibility of re-emergence of highly virulent strains. Here, we identified protocadherin 10 (PCDH10), as a cellular receptor for WEEV. We show that multiple highly virulent ancestral WEEV strains isolated in the 1930s–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, while most of the WEEV strains we examined bind to PCDH10, a contemporary strain 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-mediated infection of primary murine 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.