Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA.
Nat Commun. 2023 Jul 24;14(1):4454. doi: 10.1038/s41467-023-40126-y.
Andes virus (ANDV) and Sin Nombre virus (SNV) are the etiologic agents of severe hantavirus cardiopulmonary syndrome (HCPS) in the Americas for which no FDA-approved countermeasures are available. Protocadherin-1 (PCDH1), a cadherin-superfamily protein recently identified as a critical host factor for ANDV and SNV, represents a new antiviral target; however, its precise role remains to be elucidated. Here, we use computational and experimental approaches to delineate the binding surface of the hantavirus glycoprotein complex on PCDH1's first extracellular cadherin repeat domain. Strikingly, a single amino acid residue in this PCDH1 surface influences the host species-specificity of SNV glycoprotein-PCDH1 interaction and cell entry. Mutation of this and a neighboring residue substantially protects Syrian hamsters from pulmonary disease and death caused by ANDV. We conclude that PCDH1 is a bona fide entry receptor for ANDV and SNV whose direct interaction with hantavirus glycoproteins could be targeted to develop new interventions against HCPS.
安第斯病毒（ANDV）和圣尼诺病毒（SNV）是北美的严重汉坦病毒心肺综合征（HCPS）的病原体，目前尚无获得 FDA 批准的对策。原钙黏蛋白 1（PCDH1）是钙黏蛋白超家族蛋白，最近被确定为 ANDV 和 SNV 的关键宿主因子，代表了一个新的抗病毒靶点；然而，其确切作用仍有待阐明。在这里，我们使用计算和实验方法来描绘汉坦病毒糖蛋白复合物在 PCDH1 的第一个细胞外钙黏蛋白重复结构域上的结合表面。引人注目的是，该 PCDH1 表面上的单个氨基酸残基影响 SNV 糖蛋白-PCDH1 相互作用和细胞进入的宿主种特异性。该残基和相邻残基的突变可显著保护叙利亚仓鼠免受 ANDV 引起的肺疾病和死亡。我们得出结论，PCDH1 是 ANDV 和 SNV 的真正进入受体，其与汉坦病毒糖蛋白的直接相互作用可能成为开发针对 HCPS 的新干预措施的靶点。
