Researcher Institute of Science Tokyo Kyoto, Kyoto, Japan
Abstract: Respiratory syncytial virus (RSV) infection is a seasonal respiratory infection that mainly infects younger children, leading to lower respiratory tract disease with dyspnea in severe cases. Despite the fact there are many patients, our understanding of RSV infection pathophysiology remains limited, and thus the development of antiviral drugs is still insufficient. To resolve this issue, the development of RSV infection models is necessary. Although cell lines such as HEp-2 cells, which are highly susceptible to RSV, have been widely used in RSV research, it is difficult to precisely evaluate host response of human respiratory tract. In this study, we investigated whether our human iPS cell-derived respiratory organoids, which contain not only respiratory epithelial cells but also immune cells, fibroblasts, and vascular endothelial cells, have the potential to recapitulate host responses in the human respiratory tract during RSV infection and to be applied in drug discovery. Firstly, respiratory organoids were infected with RSV and analyzed at 4 days post infection. The high expression level of viral genome and viral protein was observed in the infected respiratory organoids. Histological analysis showed that RSV infection induced respiratory epithelial layer destruction and collagen accumulation. In addition, the concentration of pro-inflammatory cytokines in culture supernatants of respiratory organoids was increased by RSV infection. These results suggest that respiratory organoids can be used to analyze host responses in RSV infection, including inflammatory responses. Next, the efficacy of monoclonal antibodies and ribavirin against RSV was investigated using respiratory organoids. Nirsevimab, palivizumab, suptavumab, and clesrovimab significantly inhibited RSV infection at low concentrations ( < 10 ng/mL), whereas low-concentration ribavirin ( < 10 μM) did not. These results suggested that respiratory organoids could not only mimic pathological conditions of RSV infection but also evaluate the antiviral effect of monoclonal antibodies and compounds against RSV.
Funding Source: This research was supported by the iPS Cell Research Fund, the Mitsubishi Foundation, Japan Society for the Promotion of Science (JSPS), and Japan Agency for Medical Research and Development (AMED).
