Shifts in receptors during submergence of an encephalitic arbovirus

• 成果类型: Article
• 署名作者: Li, Wanyu; Plante, Jessica A.; Lin, ChieYu; Basu, Himanish; Plung, Jesse S.; Fan, Xiaoyi; Boeckers, Joshua M.; Oros, Jessica; Buck, Tierra K.; Anekal, Prajul, V; Hanson, Wesley A.; Varnum, Haley; Wells, Adrienne; Mann, Colin J.; Tjang, Laurentia, V; Yang, Pan; Reyna, Rachel A.; Mitchell, Brooke M.; Shinde, Divya P.; Walker, Jordyn L.; Cho, So Yoen; Brusic, Vesna; Llopis, Paula Montero; Weaver, Scott C.; Umemori, Hisashi; Chitnis, Isaac M.; Plante, Kenneth S.; Abraham, Jonathan
• 署名单位: Harvard University; Harvard Medical School; University of Texas System; University of Texas Medical Branch Galveston; University of Texas System; University of Texas Medical Branch Galveston; University of Texas System; University of Texas Medical Branch Galveston; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4138
• DOI: 10.1038/s41586-024-07740-2
• 发表日期: 2024-08-15
• 页码: 614-+
• 关键词: western-equine-encephalitis; garter snakes; ldl receptor; virus; encephalomyelitis; CONSTRUCTION; degradation; expression; reveals; strains

摘要

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(1-3). The basis for this phenotypic change in WEEV strains and coincident decrease in epizootic activity (known as viral submergence(3)) 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(4). 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.