Single-Nucleotide Polymorphisms in Human NPC1 Influence Filovirus Entry Into Cells
Single-Nucleotide Polymorphisms in Human NPC1 Influence Filovirus Entry Into Cells
复制标题
DOI：
10.1093/infdis/jiy248
复制
发表时间：
2018-12-15
影响因子：
6.4
通讯作者：
Takada, Ayato
中科院分区：
文献类型：
--
作者：
Kondoh, Tatsunari;Letko, Michael;Takada, Ayato
尼曼-匹克C1（NPC 1）是一种参与丝状病毒包膜糖蛋白（GP）介导的进入细胞的宿主受体，被认为是细胞对丝状病毒感染易感性的主要决定因素。已知蛋白水解消化的埃博拉病毒（EBOV）GP与NPC 1的结构域C中的2个突出环相互作用。使用先前发表的结构数据和国家生物技术信息中心单核苷酸多态性（SNP）数据库，我们确定了10个自然发生的错义SNP在人类NPC 1。为了研究这些SNP是否影响细胞对丝状病毒感染的易感性，我们产生了稳定表达具有SNP取代的NPCl的Vero E6细胞系，并比较了它们对用丝状病毒GP假型化的水泡性口炎病毒和感染性EBOV的易感性。我们发现，一些取代导致对丝状病毒的易感性降低，如病毒的较低滴度和较小的空斑/病灶大小所示。我们的数据表明，人类NPC 1 SNP可能会影响宿主对丝状病毒的易感性。
Niemann-Pick C1 (NPC1), a host receptor involved in the envelope glycoprotein (GP)-mediated entry of filoviruses into cells, is believed to be a major determinant of cell susceptibility to filovirus infection. It is known that proteolytically digested Ebola virus (EBOV) GP interacts with 2 protruding loops in domain C of NPC1. Using previously published structural data and the National Center for Biotechnology Information Single-Nucleotide Polymorphism (SNP) database, we identified 10 naturally occurring missense SNPs in human NPC1. To investigate whether these SNPs affect cell susceptibility to filovirus infection, we generated Vero E6 cell lines stably expressing NPC1 with SNP substitutions and compared their susceptibility to vesicular stomatitis virus pseudotyped with filovirus GPs and infectious EBOV. We found that some of the substitutions resulted in reduced susceptibility to filoviruses, as indicated by the lower titers and smaller plaque/focus sizes of the viruses. Our data suggest that human NPC1 SNPs may likely affect host susceptibility to filoviruses.