Layers of defense: protection from respiratory viruses by epithelial-intrinsic immunity

A central challenge in defending mucosal barriers is protecting against pathogens while also limiting excessive inflammation. Respiratory viruses are a prime example — respiratory viruses present a threat to their target cells, the epithelial cells that line the airways, but excessive leukocyte recruitment to fight the infection can lead to inflammation and respiratory distress. This review focuses on how epithelial-intrinsic defenses contribute to achieving a balanced antiviral response by adding ‘layers of defense’ that engage in sequence to control infections. Layers include: (1) secreting a defensive extracellular barrier, (2) directly blocking viral replication through cell-intrinsic effector mechanisms, (3) amplifying cell-intrinsic defenses within the epithelium through Type III interferons and other epithelial-specific mechanisms, and (4) coordinating leukocyte recruitment and activation. Recent findings in humans and organoid models support the idea that the ‘layers of defense’ created by epithelial-intrinsic mechanisms frequently and successfully counteract respiratory virus infections and limit their health impact.