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Infect. Immun. doi:10.1128/IAI.00046-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Human Lung Innate Immune Response to Bacillus anthracis Spore Infection

Pulmonary and Critical Care Division, Department of Medicine, and Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, and Programs in Immunology and Cancer, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104

^* To whom correspondence should be addressed. Email: jordan-metcalf{at}ouhsc.edu.

	Abstract

Bacillus anthracis, the causative agent of inhalational anthrax, enters a host through the pulmonary system before dissemination. We have previously shown that human alveolar macrophages participate in the initial innate immune response to B. anthracis spores through cell signal-mediated cytokine release. We proposed that the lung epithelia also participate in the innate immune response to this pathogen, and we have developed a human lung slice model to study this process. Exposure of our model to Bacillus anthracis (Sterne) spores rapidly activated the mitogen activated protein kinase signaling (MAPK) pathways ERK, p38, and JNK. In addition, RNase protection assay showed induction of mRNA of several cytokines and chemokines. This finding was reflected at the translational level with a protein peak fold increase of 3, 25, 9, 34, and 5, of IL-6, TNF-, IL-8, MIP-1 / and MCP-1 respectively, as determined by ELISA. Inhibition of individual pathways by UO126, SP600125, and SB0203580 decreased induction of chemokines and cytokines by spores, but this depended on the pathways inhibited and the cytokines and chemokines induced. Combining all three inhibitors reduced induction of all cytokines and chemokines tested to background levels. Immunohistochemistry for IL-6 and IL-8 revealed that alveolar epithelial cells and macrophages, and a few interstitial cells are the source of the cytokines and chemokines. Taken together, these data showed activation of pulmonary epithelium in response to Bacillus anthracis spore exposure. Thus, the lung epithelia actively participate in the innate immune response to Bacillus anthracis infection through cell signal-mediated elaboration of cytokines and chemokines.

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