Scheme for virus-inducible EGFR- and IL-13–dependent pathways controlling epithelial host response and remodeling. EGFR activation with receptor dimerization and receptor tyrosine kinase phosphorylation leads to Gab1 recruitment followed by PI3K activation that causes generation of phosphatidylinositol-3,4,5-phosphate (PI-3,4,5-P₃) and activation of PDK1/2 and then Akt that inactivates proapoptotic factors at the level of the mitochondria and promote cell survival. IL-13 signaling activates IRS1/2-dependent cascade to ERK1/2 and Stat6, which each contribute to upregulation of genes (CLCA and MUC) that promote cilia to goblet cell transdifferentiation. Under physiologic conditions, these pathways may (in conjunction with IFN-dependent activation of Stat1) lead to protection from viral infection, but if there is persistent activation in a susceptible genetic background, the same pathways may lead to ciliated cell hyperplasia and goblet cell metaplasia. Rational use of specific inhibitors, e.g., EGFR and IL-13R blockers, may fully restore normal epithelial architecture. Grb2, growth factor receptor–bound 2; PTEN, phosphatase and tensin homologue deleted on chromosome 10; Sos, son-of-sevenless.