Stimulated innate resistance of lung epithelium protects mice broadly against bacteria and fungi

Scott E. Evans, Brenton L. Scott, Cecilia G. Clement, Derek T. Larson, Dimitrios Kontoyiannis, Russell E. Lewis, P. Rocco Lasala, Jennifer Pawlik, Johnny Peterson, Ashok Chopra, Gary Klimpel, Gabriela Bowden, Magnus Höök, Yi Xu, Michael J. Tuvim, Burton F. Dickey

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

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-κB, 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.

Original languageEnglish (US)
Pages (from-to)40-50
Number of pages11
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume42
Issue number1
DOIs
StatePublished - Jan 1 2010

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Pathogens
Fungi
Bacteria
Epithelium
Lung
Chemical activation
Pneumonia
Cytokines
Epithelial Cells
Pneumococcal Pneumonia
Aspergillus
Mucosal Immunity
Aspergillus fumigatus
Gene expression
Adaptive Immunity
Neutropenia
Interleukin-6
Innate Immunity
Respiratory Tract Infections
Genes

Keywords

  • Immunocompromised host
  • Innate immunity
  • Lung epithelium
  • Pneumonia

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Evans, S. E., Scott, B. L., Clement, C. G., Larson, D. T., Kontoyiannis, D., Lewis, R. E., ... Dickey, B. F. (2010). Stimulated innate resistance of lung epithelium protects mice broadly against bacteria and fungi. American Journal of Respiratory Cell and Molecular Biology, 42(1), 40-50. https://doi.org/10.1165/rcmb.2008-0260OC

Stimulated innate resistance of lung epithelium protects mice broadly against bacteria and fungi. / Evans, Scott E.; Scott, Brenton L.; Clement, Cecilia G.; Larson, Derek T.; Kontoyiannis, Dimitrios; Lewis, Russell E.; Lasala, P. Rocco; Pawlik, Jennifer; Peterson, Johnny; Chopra, Ashok; Klimpel, Gary; Bowden, Gabriela; Höök, Magnus; Xu, Yi; Tuvim, Michael J.; Dickey, Burton F.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 42, No. 1, 01.01.2010, p. 40-50.

Research output: Contribution to journalArticle

Evans, SE, Scott, BL, Clement, CG, Larson, DT, Kontoyiannis, D, Lewis, RE, Lasala, PR, Pawlik, J, Peterson, J, Chopra, A, Klimpel, G, Bowden, G, Höök, M, Xu, Y, Tuvim, MJ & Dickey, BF 2010, 'Stimulated innate resistance of lung epithelium protects mice broadly against bacteria and fungi', American Journal of Respiratory Cell and Molecular Biology, vol. 42, no. 1, pp. 40-50. https://doi.org/10.1165/rcmb.2008-0260OC
Evans, Scott E. ; Scott, Brenton L. ; Clement, Cecilia G. ; Larson, Derek T. ; Kontoyiannis, Dimitrios ; Lewis, Russell E. ; Lasala, P. Rocco ; Pawlik, Jennifer ; Peterson, Johnny ; Chopra, Ashok ; Klimpel, Gary ; Bowden, Gabriela ; Höök, Magnus ; Xu, Yi ; Tuvim, Michael J. ; Dickey, Burton F. / Stimulated innate resistance of lung epithelium protects mice broadly against bacteria and fungi. In: American Journal of Respiratory Cell and Molecular Biology. 2010 ; Vol. 42, No. 1. pp. 40-50.
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