Airway epithelial versus immune cell STAT‐1 function for innate defense against respiratory viral infection

Abstract

The epithelial surface is often proposed to actively participate in host defense, but the evidence remains circumstantial. Here we use a mouse paramyxovirus (Sendai virus; SeV) to show that a prominent early event in respiratory infection is activation of Stat1 in airway epithelial cells. Stat1−/– mice developed illness that resembled severe paramyxoviral respiratory infection in humans and was characterized by increased viral replication and neutrophilic inflammation in concert with overproduction of TNF‐α and MIP‐2. Poor control of viral replication as well as TNF‐α and MIP‐2 overproduction were mimicked by infection of Stat1−/– airway epithelial cells in vitro. TNF‐α drives the MIP‐2 response, since it can be reversed by TNF‐α blockade both in vitro and in vivo. These findings pointed to an epithelial defect in Stat1−/– mice. Indeed, Stat1−/– mice reconstituted with wild‐type bone marrow were still susceptible to infection with SeV whereas wild‐type mice that received Stat1−/– bone marrow retained resistance to infection. The susceptible epithelial Stat1−/– chimeric mice also exhibited increased viral replication as well as excessive neutrophils, MIP‐2, and TNF‐α in the airspace. These findings provide some of the most definitive evidence for the role of barrier epithelial cells in innate immunity to common pathogens, particularly in controlling viral replication. Funding: NIH & Parker B. Francis Foundation