At mucosal barriers, the best outcome for the host requires a balance between defending against harmful exposures while also avoiding excessive inflammation, which can compromise organ function. Constitutive and inducible innate immune defenses at the site of infection are critical to achieving this balance. Innate immunity at mucosal surfaces (e.g. respiratory, digestive, and reproductive tracts) includes the secretion of protective mucus and, for pathogens that penetrate this first line of defense, engagement of innate immune sensors on the cells that comprise the tissue barrier (e.g. epithelial cells, fibroblasts), as well as local innate immune cells (e.g. NK cells, neutrophils, macrophages). Innate immune signaling activates direct antipathogen effector mechanisms along with cytokine production and antigen presentation by local cells that promote additional leukocyte recruitment and adaptive immunity.

Within this canonical paradigm, epithelial cells play a specialized role as the cells that form the barrier between the body and the external environment. The epithelium is not a passive barrier — like innate leukocytes, epithelial cells mount robust constitutive and inducible defenses to protect tissue integrity. In the airways, the focus of this review, while pathogen defense is paramount, excessive immune responses and accompanying inflammation can lead to wheezing and respiratory distress. Epithelial innate immune defenses help achieve an optimal balance through ‘layers of defense’ — sequential engagement of host defenses to remove the threat with the minimum leukocyte recruitment and activation needed, and no more. Recent evidence supports the idea that intrinsic antiviral defenses of the epithelium are dynamically engaged during exposures to common viral infections and can often contain these infections without symptoms.