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 用于医疗保健就诊。在大多数受影响的人中，轮状病毒感染的症状是轻微的和自我限制的。 然而，在慢性鼻-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种在成人中很常见，并且RV-C感染 与研究充分的RV-A和RV-B相比，导致更严重的鼻腔症状。我们也 确定rs6967330是最近发现的RV-C钙粘附素相关家族的遗传风险变异体 成员3(CDHR3)病毒受体导致成人CRS的几率增加两倍。尽管CRS是一个 异质性疾病，手术组织的转录组研究确定了显著的失调 与趋化因子/细胞因子信号和上皮-间充质转化(EMT)相关的基因。这个 本应用的目的是(I)确定患有CRS和rs6967330 CDHR3风险等位基因的受试者 与RV-C感染相比，RV-C感染具有不同的分子内型 更频繁的野生型等位基因和(Ii)确定携带rs6967330等位基因的成年CRS受试者是否更多 与RV-A和RV-B感染相比，RV-C感染可能导致CRS恶化。我们 假设具有rs6967330 CDHR3风险等位基因的空气-液体-界面(ALI)培养的体外研究将 产生分子内型，其特征是(I)RV-C结合和复制增加，ii)增加 与1型和2型免疫相关的细胞因子/趋化因子，以及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，EMT通路与呼吸道重塑有关。 同样，我们假设我们对携带rs6967330等位基因的CRS受试者的体内研究将揭示一种 继发于RV-C感染的CRS恶化的数量增加，其特征是 感染后的鼻腔症状、鼻腔细胞因子的产生和转录改变。 迫切需要了解导致猪细小病毒致病性增强的分子机制 携带rs6967330 CDHR3风险等位基因的RV-C感染通知新靶点的发展 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.