Improve Lung Regeneration Through Targeting Tuft Cells Following Viral Infection

ABSTRACT Seasonal influenza and the current COVID-19 pandemic cause serious health and financial burdens. Severe viral infection leads to acute lung injury, inflammation and contributes to tissue remodeling and fibrosis. Intriguingly, clusters of ectopic basal cells (also known as pod cells) are present in the peripheral lungs during acute infection and remodeling phases. Initial studies indicated that these cells were able to generate type I and II alveolar epithelial cells (AECs). Nevertheless, subsequent lineage tracing studies revealed that pod cells had minimal if any contribution to alveolar regeneration. Moreover, our preliminary data suggest that pod cells give rise to goblet cells, resulting in mucous metaplasia accompanied by the presence of chemosensory tuft cells (also known as brush cells). Significantly, genetic ablation of tuft cells promotes the differentiation of pod cells into AECs. Our further analyses revealed that tuft cells express the Notch ligand Jag2, whereas pod cells express Notch receptors with prominent Notch activation. Consistently, Notch inhibition led to reduced mucous metaplasia and improved alveolar regeneration. We therefore hypothesize that tuft cells promote mucous metaplasia of pod cells and impede alveolar regeneration via paracrine JAG2/Notch activation upon viral infection. Two specific aims were devised to test the hypothesis. Aim1: To address the molecular mechanisms by which tuft cells promote mucous metaplasia following viral infection. Aim2: To promote the differentiation of pod cells into AECs through targeting JAG2 in tuft cells. In this aim we will combine a novel COVID-19 mouse model and pod cell organoids established from COVID-19 patient lungs to test the efficacy of a JAG/Notch decoy in promoting alveolar regeneration. Together this proposal will not only elucidate the disease mechanisms impairing lung regeneration post viral infection, but also offer new therapeutic approaches to treat lungs infected by influenza and coronavirus.