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Stimulated Innate Resistance of Lung Epithelium Protects Mice Broadly against Bacteria and Fungi

¹ Department of Pulmonary Medicine, ² Department of Molecular Pathology, and ³ Department of Infectious Diseases, University of Texas, M. D. Anderson Cancer Center, Houston, Texas; ⁴ Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas; ⁵ Center for Lung Inflammation and Infection, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas

Correspondence and requests for reprints should be addressed to Scott E. Evans, M.D., Department of Pulmonary Medicine, Unit 403, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009. E-mail: seevans{at}mdanderson.org

Pneumonia is a serious problem worldwide. We recently demonstrated that innate defense mechanisms of the lung are highly inducible against pneumococcal pneumonia. To determine the breadth of protection conferred by stimulation of lung mucosal innate immunity, and to identify cells and signaling pathways activated by this treatment, mice were treated with an aerosolized bacterial lysate, then challenged with lethal doses of bacterial and fungal pathogens. Mice were highly protected against a broad array of Gram-positive, Gram-negative, and class A bioterror bacterial pathogens, and the fungal pathogen, Aspergillus fumigatus. Protection was associated with rapid pathogen killing within the lungs, and this effect was recapitulated in vitro using a respiratory epithelial cell line. Gene expression analysis of lung tissue showed marked activation of NF-B, type I and II IFN, and antifungal Card9-Bcl10-Malt1 pathways. Cytokines were the most strongly induced genes, but the inflammatory cytokines TNF and IL-6 were not required for protection. Lung-expressed antimicrobial peptides were also highly up-regulated. Taken together, stimulated innate resistance appears to occur through the activation of multiple host defense signaling pathways in lung epithelial cells, inducing rapid pathogen killing, and conferring broad protection against virulent bacterial and fungal pathogens. Augmentation of innate antimicrobial defenses of the lungs might have therapeutic value for protection of patients with neutropenia or impaired adaptive immunity against opportunistic pneumonia, and for defense of immunocompetent subjects against a bioterror threat or epidemic respiratory infection.

Key Words: innate immunity • pneumonia • immunocompromised host • lung epithelium

CLINICAL RELEVANCE Pneumonia results in significant worldwide mortality. Stimulating antimicrobial signaling to induce broad protection against respiratory pathogens has novel scientific and clinical implications for protection against opportunistic, bioterror, and epidemic infections.

 

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