Influenza pathogenesis: Club cells take the “cure”

The illness that follows influenza A virus (IAV) infection results from both direct effects of IAV replication in the respiratory tract (RT) and from sequelae of the host immune response. The virus directly induces apoptosis or necrosis of infected RT cells and NK cells, CD8 T cells lyse infected cells, and damaging inflammatory mediators are produced by various infiltrating immune cells. Accordingly, the degree of RT pathology is believed to reflect both the extent of virus replication and the magnitude of the host immune response. In this issue, however, Heaton et al. provide evidence for a novel mechanism of IAV pathogenesis. They find that a small fraction of a particular RT cell type, the club cell, can “cure” itself of IAV but continue to produce inflammatory mediators, which may contribute to sustained RT inflammation and injury following IAV clearance.

Heaton et al. adapted a strategy to indelibly mark IAV-infected cells where any cell infected by the virus will express RFP. Contrary to expectation, they detected RFP⁺ cells in the RT up to day 21 post-infection (p.i.), long after virus-infected cells are cleared. The authors identify these residual RFP⁺ cells as club cells—bronchiolar (small airway) exocrine cells (formerly known as Clara cells), which secrete products that protect the small airways.

Remarkably, by day 10 p.i. the residual RFP⁺ club cells were “cured,” that is, they no longer expressed detectable viral RNA. But they retained the type I interferon stimulated gene expression signature of infected cells and production of inflammatory chemokines, suggesting that these cells may contribute to RT pathology. Supporting this idea, selective depletion of the residual RFP⁺ cells diminished epithelial cell damage in the RT. However, severe RT injury with lethal outcome is associated with infection of alveolar epithelial cells, which are not “cured” in this model, so the contribution of club cells in IAV pathogenesis remains to be determined.

These provocative findings raise many questions, notably, how do infected club cells escape destruction by IAV and recognition by NK cells or CD8 CTL? Also, what sustains the inflammatory signature of club cells after viral RNA elimination? Nevertheless, these results provide a potential explanation for persistent RT inflammation following virus clearance and may presage the development of new strategies to treat the sequelae of IAV infection.