Human rhinovirus (RV) is a major risk factor for chronic obstructive pulmonary disease (COPD) and asthma exacerbations. The exploration of RV pathogenesis has been hampered by a lack of disease-relevant model systems. We performed a detailed characterization of host responses to RV infection in human lung tissue ex vivo and investigated whether these responses are disease relevant for patients with COPD and asthma. In addition, impact of the viral replication inhibitor rupintrivir was evaluated. Human precision-cut lung slices (PCLS) were infected with RV1B with or without rupintrivir. At Days 1 and 3 after infection, RV tissue localization, tissue viability, and viral load were determined. To characterize host responses to infection, mediator and whole genome analyses were performed. RV successfully replicated in PCLS airway epithelial cells and induced both antiviral and proinflammatory cytokines such as IFNα2a, CXCL10, CXCL11, IFN-γ, TNFα, and CCL5. Genomic analyses revealed that RV not only induced antiviral immune responses but also triggered changes in epithelial cell–associated pathways. Strikingly, the RV response in PCLS was reflective of gene expression changes described in patients with COPD and asthma. Although RV-induced host immune responses were abrogated by rupintrivir, RV-triggered epithelial processes were largely refractory to antiviral treatment. Detailed analysis of RV-infected human PCLS and comparison with gene signatures of patients with COPD and asthma revealed that the human RV PCLS model represents disease-relevant biological mechanisms that can be partially inhibited by a well-known antiviral compound and provide an outstanding opportunity to evaluate novel therapeutics.

人鼻病毒 (RV) 是慢性阻塞性肺病 (COPD) 和哮喘发作的主要危险因素。由于缺乏与疾病相关的模型系统，RV 发病机制的探索受到了阻碍。我们对体外人肺组织中宿主对 RV 感染的反应进行了详细的表征并调查了这些反应是否与 COPD 和哮喘患者的疾病相关。此外，还评估了病毒复制抑制剂 rupintrivir 的影响。在有或没有 rupintrivir 的情况下，人类精确切割的肺切片 (PCLS) 被 RV1B 感染。在感染后第 1 天和第 3 天，确定了 RV 组织定位、组织活力和病毒载量。为了表征宿主对感染的反应，进行了介质和全基因组分析。RV 在 PCLS 气道上皮细胞中成功复制并诱导抗病毒和促炎细胞因子，如 IFNα2a、CXCL10、CXCL11、IFN-γ、TNFα 和 CCL5。基因组分析显示，RV 不仅诱导抗病毒免疫反应，还引发上皮细胞相关通路的变化。引人注目的是，PCLS 中的 RV 反应反映了 COPD 和哮喘患者中描述的基因表达变化。尽管 rupintrivir 消除了 RV 诱导的宿主免疫反应，但 RV 触发的上皮过程在很大程度上对抗病毒治疗无效。对 RV 感染的人类 PCLS 的详细分析以及与 COPD 和哮喘患者的基因特征的比较表明，人类 RV PCLS 模型代表了与疾病相关的生物学机制，可以被一种众所周知的抗病毒化合物部分抑制，并提供了一个绝佳的机会评估新疗法。