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

Abstract

Human rhinovirus (HRV) is a main cause of airway infections and a major risk factor of exacerbations in asthma and COPD. Exploration of HRV pathogenesis has been hampered by the lack of complex in vitro models that closely represent the human disease. Aim of the study was to characterize the immune response of human lung tissue to ex vivo HRV infection using Precision-Cut Lung Slices (PCLS). Human PCLS containing airways were inoculated with HRV1B, UV-inactivated HRV, medium or HRV in presence of Rupintrivir. At 1d and 3d post infection (p.i.) tissue vitality, viral load and cytokine levels were measured and transcriptomic analyses upon RNA isolation from PCLS were performed. HRV infection of human PCLS exerted 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 1d or 3d p.i., respectively. These gene signatures were indicative of interferon signaling, epithelial cell differentiation, lymphocyte regulation, antigen presentation and NK cell cytotoxicity. Rupintrivir downregulated about 1/3 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 impaired by Rupintrivir. In conclusion, ex vivo infection of human lung tissue with HRV induced a strong antiviral and pro-inflammatory immune response. The observed gene regulation profile revealed involvement of epithelial but also multiple immune cells. This enables us to study HRV induced immune responses in the human lung microenvironment.