Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 42, Issue 1, Pages 40-50Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2008-0260OC
Keywords
innate immunity; pneumonia; immunocompromised host; lung epithelium
Funding
- University of Texas, M. D. Anderson Cancer Center
- National Institutes of Health (NIH) [HL072984, AI5385802, AI30065, AI064389, AI15437, CA105352, CA016672]
- US Army [170210699]
- U.S. Department of Health and Human Services/NIH Cancer Center [P30CA16672]
- NIH National Center for Research Resources [KL2-RR-02419]
- NATIONAL CANCER INSTITUTE [U01CA105352, P30CA016672] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR002419] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL072984] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [U01AI082226, R01AI064389, U01AI053858, R13AI030065] Funding Source: NIH RePORTER
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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-kappa B, type I and 11 IFN, and antifungal Card9-Bcl70-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.
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