Fan Xiaoyi, Li Wanyu, Oros Jessica, Plante Jessica A, Mitchell Brooke M, Plung Jesse S, Basu Himanish, Nagappan-Chettiar Sivapratha, Boeckers Joshua M, Tjang Laurentia V, Mann Colin J, Brusic Vesna, Buck Tierra K, Varnum Haley, Yang Pan, Malcolm Linzy M, Choi So Yoen, de Souza William M, Chiu Isaac M, Umemori Hisashi, Weaver Scott C, Plante Kenneth S, Abraham Jonathan
Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
Cell. 2025 May 29;188(11):2957-2973.e28. doi: 10.1016/j.cell.2025.03.029. Epub 2025 Apr 4.
Western equine encephalitis virus (WEEV) is an arbovirus that historically caused large outbreaks of encephalitis throughout the Americas. WEEV binds protocadherin 10 (PCDH10) as a receptor, and highly virulent ancestral WEEV strains also bind low-density lipoprotein receptor (LDLR)-related proteins. As WEEV declined as a human pathogen in North America over the past century, isolates have lost the ability to bind mammalian receptors while still recognizing avian receptors. To explain shifts in receptor dependencies and assess the risk of WEEV re-emergence, we determined cryoelectron microscopy structures of WEEV bound to human PCDH10, avian PCDH10, and human very-low-density lipoprotein receptor (VLDLR). We show that one to three E2 glycoprotein substitutions are sufficient for a nonpathogenic strain to regain the ability to bind mammalian receptors. A soluble VLDLR fragment protects mice from lethal challenge by a virulent ancestral WEEV strain. Because WEEV recently re-emerged in South America after decades of inactivity, our findings have important implications for outbreak preparedness.
西部马脑炎病毒（WEEV）是一种虫媒病毒，历史上曾在美洲引发过大规模脑炎疫情。WEEV将原钙黏蛋白10（PCDH10）作为受体，高毒力的WEEV祖先毒株还能结合低密度脂蛋白受体（LDLR）相关蛋白。在过去一个世纪里，随着WEEV作为人类病原体的情况在北美减少，分离株已失去结合哺乳动物受体的能力，但仍能识别禽类受体。为了解释受体依赖性的变化并评估WEEV重新出现的风险，我们确定了与人类PCDH10、禽类PCDH10和人类极低密度脂蛋白受体（VLDLR）结合的WEEV的冷冻电子显微镜结构。我们发现，一到三个E2糖蛋白取代足以使非致病性毒株重新获得结合哺乳动物受体的能力。可溶性VLDLR片段可保护小鼠免受高毒力的WEEV祖先毒株的致命攻击。由于WEEV在数十年不活跃后最近在南美洲重新出现，我们的研究结果对疫情防范具有重要意义。
