Rhinovirus-induced Human Lung Tissue Responses Mimic COPD and Asthma Gene Signatures

Human rhinovirus (RV) is a major risk factor for COPD and asthma exacerbations. 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 day 1 and 3 post-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 anti-viral and pro-inflammatory cytokines such as IFNα2a, CXCL10, CXCL11, IFN-γ, TNFα and CCL5. Genomic analyses revealed that RV not only induced anti-viral 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 COPD and asthma patients. While 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 COPD and asthma patient gene signatures 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. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).