RSV is a major respiratory pathogen, particularly among young children, causing severe lower respiratory tract diseases. While current models, such as HEp-2 cells, are commonly used for RSV research, they do not accurately mimic the complex responses of the human respiratory system. The researchers aimed to evaluate the utility of respiratory organoids, which are more representative of the in vivo human respiratory tract due to the presence of various cell types, in advancing our understanding of RSV pathophysiology and evaluating therapeutic and preventive drugs.

The study revealed that RSV efficiently infected the iPS cell-derived respiratory organoids, leading to high viral replication and protein expression. The infected organoids displayed respiratory epithelial layer damage, collagen accumulation, and increased levels of pro-inflammatory cytokines like IL-8 and IFN-γ. Additionally, whereas the researchers found that monoclonal antibodies such as nirsevimab, palivizumab, and others targeting the RSV F protein were highly effective in inhibiting RSV replication, ribavirin--an antiviral previously used for RSV treatment--showed minimal efficacy. This result highlights the limitations of ribavirin in the organoid model and suggests that newer antiviral agents or antibodies may be more promising.

The research team also used RNA sequencing and other assays to investigate the host response to RSV infection. RSV-induced changes included a robust innate immune response and the activation of genes associated with interferon signaling. These findings demonstrate the organoids' ability to replicate the inflammatory and immune responses typically seen during RSV infection in humans. Moreover, the organoids allowed for detailed analysis of cellular interactions and responses, offering an advanced platform for evaluating the effects of antiviral treatments and antibodies on different cell types within the respiratory tract.

This study emphasizes the importance of using human iPS cell-derived respiratory organoids for modeling RSV infection. The results suggest that these organoids are a valuable tool for studying the virus's pathophysiology, testing therapeutic interventions, and advancing the development of effective drugs. Furthermore, the study indicates that these models could be utilized to evaluate the efficacy of vaccines and other treatments, providing a more accurate reflection of the human respiratory environment compared to traditional models. The research also suggests that incorporating additional immune cell types, such as T cells and neutrophils, may further enhance the model's ability to replicate the complexities of RSV infection, especially in the context of severe inflammation.

• doi: 10.26508/lsa.202402837