Epithelial Plasticity and Innate Immune Activation Promote Lung Tissue Remodeling following Respiratory Viral Infection

Beppu, Andrew K.; Zhao, Juanjuan; Yao, Changfu; Carraro, Gianni; Israely, Edo; Coelho, Anna Lucia; Hogaboam, Cory M; Parks, William C.; Kolls, Jay K.; Stripp, Barry R.

Epithelial plasticity has been suggested in lungs of mice following genetic depletion of stem cells but is of unknown physiological relevance. Viral infection and chronic lung disease share similar pathological features of stem cell loss in alveoli, basal cell (BC) hyperplasia in small airways, and innate immune activation, that contribute to epithelial remodeling and loss of lung function. We show that a novel lineage of distal airway secretory cells, intralobar serous (IS) cells, are activated to assume BC fates following influenza virus infection. Nascent BC differ from pre-existing BC by high expression of IL-22ra1 and undergo IL-22-dependent expansion for colonization of injured alveoli. Resolution of virus-elicited inflammation resulted in BC>IS re-differentiation in repopulated alveoli, and increased local expression of antimicrobial factors, but failed to replace normal alveolar epithelium. Epithelial plasticity therefore protects against mortality from acute respiratory viral infection but results in distal lung remodeling and loss of lung function.