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^1,2,3. 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.

西方马脑炎病毒（WEEV）是一种节肢动物传播的病毒（虫媒病毒），在二十世纪初经常引起人类和马的脑炎大爆发，但此后爆发频率明显下降，这种甲病毒株在过去二十年对哺乳动物的毒力比 20 世纪 30 年代和 20 世纪 40 年代分离的毒株要低^1,2,3 。 WEEV 毒株的这种表型变化以及动物流行病活性同时下降（称为病毒淹没³ ）的基础尚不清楚，高毒力毒株重新出现的可能性也不清楚。在这里，我们将原钙粘蛋白 10 (PCDH10) 确定为 WEEV 的细胞受体。我们发现，在 20 世纪 30 年代和 1940 年代分离出的多种高毒力祖先 WEEV 毒株，除了结合人类 PCDH10 外，还可以结合极低密度脂蛋白受体 (VLDLR) 和载脂蛋白 E 受体 2 (ApoER2)，这些受体可被另一种脑炎病毒识别。甲病毒作为受体⁴ 。然而，虽然我们检查的大多数WEEV毒株都与PCDH10结合，但当代毒株已经失去了识别哺乳动物PCDH10的能力，同时保留了结合鸟类受体的能力，这表明WEEV在地方性传播期间适应了主要储存宿主。 PCDH10 支持 WEEV E2-E1 糖蛋白介导的原代小鼠皮质神经元感染，给予可溶形式的 PCDH10 可以保护小鼠免受致命的 WEEV 攻击。我们的结果对于医疗对策的制定和重新出现的 WEEV 毒株的风险评估具有重要意义。