Bochkov Yury A, Watters Kelly, Ashraf Shamaila, Griggs Theodor F, Devries Mark K, Jackson Daniel J, Palmenberg Ann C, Gern James E
Department of Pediatrics and
Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI 53706.
Proc Natl Acad Sci U S A. 2015 Apr 28;112(17):5485-90. doi: 10.1073/pnas.1421178112. Epub 2015 Apr 6.
Members of rhinovirus C (RV-C) species are more likely to cause wheezing illnesses and asthma exacerbations compared with other rhinoviruses. The cellular receptor for these viruses was heretofore unknown. We report here that expression of human cadherin-related family member 3 (CDHR3) enables the cells normally unsusceptible to RV-C infection to support both virus binding and replication. A coding single nucleotide polymorphism (rs6967330, C529Y) was previously linked to greater cell-surface expression of CDHR3 protein, and an increased risk of wheezing illnesses and hospitalizations for childhood asthma. Compared with wild-type CDHR3, cells transfected with the CDHR3-Y529 variant had about 10-fold increases in RV-C binding and progeny yields. We developed a transduced HeLa cell line (HeLa-E8) stably expressing CDHR3-Y529 that supports RV-C propagation in vitro. Modeling of CDHR3 structure identified potential binding sites that could impact the virus surface in regions that are highly conserved among all RV-C types. Our findings identify that the asthma susceptibility gene product CDHR3 mediates RV-C entry into host cells, and suggest that rs6967330 mutation could be a risk factor for RV-C wheezing illnesses.
与其他鼻病毒相比，鼻病毒C（RV-C）种属的成员更易引发喘息性疾病和哮喘急性发作。此前，这些病毒的细胞受体尚不明确。我们在此报告，人类钙黏蛋白相关家族成员3（CDHR3）的表达使通常对RV-C感染不敏感的细胞能够支持病毒的结合与复制。一种编码单核苷酸多态性（rs6967330，C529Y）先前被认为与CDHR3蛋白在细胞表面的更高表达相关，并且与喘息性疾病及儿童哮喘住院风险增加有关。与野生型CDHR3相比，用CDHR3-Y529变体转染的细胞在RV-C结合及子代产量方面增加了约10倍。我们构建了一种稳定表达CDHR3-Y529的转导HeLa细胞系（HeLa-E8），该细胞系可在体外支持RV-C的增殖。CDHR3结构建模确定了可能在所有RV-C类型中高度保守的区域影响病毒表面的潜在结合位点。我们的研究结果表明，哮喘易感基因产物CDHR3介导RV-C进入宿主细胞，并提示rs6967330突变可能是RV-C引发喘息性疾病的一个风险因素。
