An epithelial integrin regulates the amplitude of protective lung interferon responses

Integrins facilitate intercellular movement and communication. Unlike the promiscuous activities of many integrins, 6 integrin is restricted to epithelia and partners exclusively with integrin V to modulate acute lung injury (ALI). Given that ALI is a complication of respiratory infection, we used mice lacking 6 integrin (6 KO) to probe the role of the epithelial layer in controlling the lung microenvironment during infection. We found 6 KO mice were protected from disease caused by influenza and Sendai virus infections. They were also protected from disease caused by Streptococcus pneumoniae infection alone and after prior influenza virus infection, the co-infection representing an often-lethal condition in humans. Resistance in the absence of epithelial 6 integrin was caused by intrinsic priming of the lung microenvironment by type I interferons through a mechanism involving transforming growth factor- regulation. Expression of 6 on epithelia suppresses the production of interferons, providing an advantage to the pathogen. Acute inhibition of 6 function may therefore provide a means to improve outcomes in lung microbial infections.

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Meliopoulos VA, Van de Velde LA, Van de Velde NC, Karlsson EA, Neale G, Vogel P, Guy C, Sharma S, Duan S, Surman SL, Jones BG, Johnson MD, Bosio C, Jolly L, Jenkins RG, Hurwitz JL, Rosch JW, Sheppard D, Thomas PG, Murray PJ, Schultz-Cherry S