Transcriptomic analyses reveal anti-viral responses of epithelial cells and multiple immune cell types in HRV infected human lung tissue

Abstract

Background: Human rhinovirus (HRV) is a main cause of airway infections and a major risk factor of exacerbations in asthma and COPD. Investigation of HRV pathogenesis has been hampered by the lack of complex in vitro models that closely represent the human disease. The aim of the study was to characterize the immune response of viable human lung tissue to ex vivo HRV infection using Precision-Cut Lung Slices (PCLS). Method: Human PCLS containing airways were inoculated with HRV1B, UV‐inactivated HRV, medium or HRV in the presence of 3C protease inhibitor Rupintrivir. At day 1 and day 3 post infection (p.i.) tissue vitality, viral load and cytokine release were measured and transcriptomic analyses upon RNA isolation from PCLS were performed. Results: HRV infection of human PCLS induced no strong cytopathic effect as indicated by intact tissue viability. The transcriptomic analyses revealed that HRV infection of PCLS induced 5977 and 4322 gene expression changes at day 1 or day 3 p.i., respectively. These gene signatures were indicative of interferon signalling, epithelial cell differentiation, lymphocyte regulation, antigen presentation and NK cell cytotoxicity. Rupintrivir downregulated about one third of the HRV upregulated genes. These data were confirmed by increased protein levels of pro‐inflammatory and anti‐viral cytokines induced by HRV, e.g. TNF‐α and IFNα2a, which were also diminished by Rupintrivir. Conclusion: In conclusion, ex vivo infection of human lung tissue with HRV induced a strong antiviral and pro‐inflammatory immune response. The observed gene expression profile revealed involvement of epithelial but also multiple immune cells. This enables us to study HRV induced immune responses in the human lung microenvironment