BACKGROUND Acute exacerbations of chronic rhinosinusitis (AECRS) are commonly triggered by rhinovirus (RV) infections with secondary bacterial infections. Risk factors for AECRS are not well understood. OBJECTIVE We sought to determine whether carriers of the minor allele rs6967330 (AA/AG) in the cadherin-related family member 3 (CDHR3) gene have an increased risk for RV infections in AECRS in vivo and identify CDHR3 genotype-dependent host responses to RV infection in differentiated nasal airway-liquid interface (ALI) cultures ex vivo. METHODS We performed a prospective year-long study of adult subjects with chronic rhinosinusitis by the rs6967330 genotype (AA/AG, n = 16; GG, n = 38). We contacted subjects every 2 weeks, and if they reported AECRS, then clinical data were collected. ALI cultures of adults with chronic rhinosinusitis (AG/AA, n = 19; GG, n = 19) were challenged with RV-A and RV-C. We measured viral copy numbers at 4 and 48 hours postinfection and RNA transcriptomes and cytokines at 48 hours postinfection. RESULTS Subjects with the minor allele had significantly higher rates of RV and bacterial infections than those with the major allele. ALI minor allele cultures had higher viral copy numbers of RV-A and RV-C after 48 hours compared with the major allele. Differentially expressed genes and pathways identified an upregulation of IL-10 and IL-4/IL-13 pathways and a significant downregulation of Toll-like receptor pathways in the minor allele cultures after RV-A and RV-C infection. Unsupervised hierarchical analysis of all differentially expressed genes suggested that allergic rhinitis had an additive effect on this response. CONCLUSIONS The rs6967330 minor allele is associated with increased RV-A and RV-C replication, downregulation of Toll-like receptor-mediated responses, and increased type-2 and cytokine and chemokine responses during RV infection.

中文翻译：

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CDHR3 中的 rs6967330 次要等位基因是慢性鼻窦炎严重急性加重的重要危险因素。


背景 慢性鼻-鼻窦炎 （AECRS） 急性加重通常由鼻病毒 （RV） 感染伴继发性细菌感染引发。AECRS 的危险因素尚不清楚。目的 我们试图确定钙粘蛋白相关家族成员 3 （CDHR3） 基因中次要等位基因 rs6967330 （AA/AG） 的携带者是否在体内 AECRS 中增加 RV 感染的风险，并在分化的鼻气道-液体界面 （ALI） 体外培养物中鉴定 CDHR3 基因型依赖性宿主对 RV 感染的反应。方法 我们通过 rs6967330 基因型 （AA/AG，n = 16;GG，n = 38）。我们每 2 周联系一次受试者，如果他们报告了 AECRS，则收集临床资料。成人慢性鼻-鼻窦炎 （AG/AA， n = 19;GG，n = 19）接受 RV-A 和 RV-C 攻击。我们测量了感染后 4 小时和 48 小时的病毒拷贝数，以及感染后 48 小时的 RNA 转录组和细胞因子。结果 具有次要等位基因的受试者的 RV 和细菌感染率显著高于具有主要等位基因的受试者。与主要等位基因相比，ALI 次要等位基因培养物在 48 小时后具有更高的 RV-A 和 RV-C 病毒拷贝数。差异表达基因和通路在 RV-A 和 RV-C 感染后次要等位基因培养物中发现 IL-10 和 IL-4/IL-13 通路的上调以及 Toll 样受体通路的显着下调。对所有差异表达基因的无监督分层分析表明，过敏性鼻炎对这种反应有累加效应。 结论 rs6967330 次要等位基因与 RV-A 和 RV-C 复制增加、Toll 样受体介导反应下调以及 RV 感染期间 2 型和细胞因子和趋化因子反应增加有关。