The role of stromal cells in the mouse model of respiratory syncytial virus infection

Abstract

Respiratory Syncytial Virus (RSV) is the single most important cause of acute lower respiratory tract infections in infants. Most children are infected with RSV by the age of two, and the majority of them suffer only a simple cold. However, 1- 3% develop severe bronchiolitis that requires hospitalisation and these children have a greater risk of developing recurrent wheeze and asthma-like symptoms in later childhood. There is currently no treatment or vaccine against RSV. Despite its prevalence, the characteristics of RSV infection and spread in the host lung are not well characterised. Stromal cells are the functionally connective tissue of the lung and include alveolar type I and II (ATI/ATII) epithelial cells, endothelial cells and fibroblasts. These cells are slowly being recognised as important players in the response to respiratory infections through their expression of proinflammatory mediators and tissue repair proteins. However, the role of stromal cells in RSV infection in vivo has not been elucidated. We have been able to identify several important chemokines, cytokines and growth factors that are expressed by stromal cells in response to RSV in vivo using fluorescent activated cell sorting and gene expression analysis. Interestingly, our data show that ATII epithelial cells are a major source of growth factors while the non-epithelial, non-endothelial stromal cells are a major source of chemokines. In addition, when infecting lung fibroblasts ex vivo with RSV, many chemokines known to be important during RSV infection are produced. We further demonstrate that expression of several of these mediators in vivo is dependent on IFNAR signalling, illustrating the cellular crosstalk between stromal cells and alveolar macrophages in the lung during RSV infection, which is needed for effective viral clearance. Finally, we highlight the potential protective role of ATII epithelial cell-derived GM-CSF expression in the lung during RSV infection in vivo. Data from these experiments reveal novel and previously unknown roles of stromal cells in the response to RSV infection in vivo and highlight new targets, which could be modulated for potential therapeutic benefits.