Interactions between RV-C and its receptor CDHR3 in the development of chronic rhinosinusitis

项目摘要 鼻病毒（RV）感染在不同年龄、性别和种族中普遍存在，是最常见的原因。 进行健康检查。在大多数受影响的人中，RV感染的症状是轻微的和自限性的。 然而，在慢性鼻窦炎（CRS）患者中，RV感染是CRS恶化的主要原因 以及相关的发病率。最近，我们发现RV-C种类在成人中很常见， 与研究充分的RV-A和RV-B物种相比，导致更严重的鼻窦症状。我们也 rs6967330是最近发现的RV-C钙粘蛋白相关家族中的一种遗传风险变异， 成员3（CDHR 3）病毒受体，导致成人CRS的几率增加两倍。虽然CRS是一个 对于异质性疾病，外科组织的转录组研究已经确定了 与趋化因子/细胞因子信号传导和上皮-间充质转化（EMT）相关的基因。的 本申请的目的是（i）确定具有CRS和rs6967330 CDHR 3风险等位基因的受试者 与那些具有RV-C感染的人相比，具有不同的分子内型， 更频繁的野生型等位基因，和（ii）确定具有rs6967330等位基因的成年CRS受试者是否更频繁地 与RV-A和RV-B感染相比，RV-C感染可能导致CRS加重。我们 假设具有rs6967330 CDHR 3风险等位基因的气液界面（ALI）培养物的体外研究将 产生分子内型，其特征在于（i）增加的RV-C结合和复制， 与1型和2型免疫相关的细胞因子/趋化因子，和iii）差异表达基因（DEG） 与表达野生型等位基因的上皮细胞相比，与气道重塑相关的EMT途径。 同样，我们假设我们对具有rs6967330等位基因的CRS受试者的体内研究将揭示一种新的基因表达。 继发于RV-C感染的CRS加重次数增加，其特征为 感染后气道重塑中的鼻窦症状、鼻内细胞因子产生和转录组学变化。 有一个关键需要了解的分子机制，增加致病性的基础， 携带rs6967330 CDHR 3风险等位基因的人中的RV-C感染，以告知新靶向治疗的发展 预防和减缓CRS进展的策略。

PROJECT ABSTRACT Rhinovirus (RV) infections are ubiquitous across age, gender, and ethnicity and are the most frequent reason for healthcare visits. In the majority of affected persons, the symptoms of RV infections are mild and self-limiting. In persons with chronic rhinosinusitis (CRS), however, RV infections are a major cause of CRS exacerbations and associated morbidity. Recently, we found that RV-C species are common in adults, and that RV-C infections result in greater sinonasal symptoms compared with the well-studied RV-A and RV-B species. We also determined that rs6967330, a genetic risk variant in the recently discovered RV-C Cadherin Related Family Member 3 (CDHR3) viral receptor, causes a two-fold increase in the odds for adult CRS. Although CRS is a heterogeneous disorder, transcriptome studies of surgical tissues have determined significant dysregulation of genes associated with chemokine/cytokine signaling and epithelial-mesenchymal transitions (EMT). The objective of this application is to (i) determine if subjects with CRS and the rs6967330 CDHR3 risk allele have a different molecular endotype in response to RV-C infections as compared with those with the more frequent wild-type allele and (ii) determine if adult CRS subjects with the rs6967330 allele are more likely to have CRS exacerbations with RV-C infections compared to RV-A and RV-B infections. We hypothesize that in vitro studies of air-liquid-interface (ALI) cultures with the rs6967330 CDHR3 risk allele will generate a molecular endotype characterized by (i) increased RV-C binding and replication, ii) increased cytokines/chemokines associated with types 1 and 2 immunity, and iii) differentially expressed genes (DEGs) and EMT pathways associated with airway remodeling compared to epithelia expressing the wild-type allele. Likewise, we hypothesize that our in vivo studies of CRS subjects with the rs6967330 allele will reveal an increased number of CRS exacerbations secondary to RV-C infections that are characterized by increased sinonasal symptoms, nasal cytokine production, and transcriptomic changes in airway remodeling after infection. There is a critical need to understand the molecular mechanisms that underlie the increased pathogenicity of RV-C infections in persons with the rs6967330 CDHR3 risk allele to inform the development of new targeted strategies to prevent and slow the progression of CRS.