Anthrax Lethal Toxin Impairs IL-8 Expression in Epithelial Cells through Inhibition of Histone H3 Modification

Lethal toxin (LT) is a critical virulence factor of Bacillus anthracis, the etiological agent of anthrax, whose pulmonary form is fatal in the absence of treatment. Inflammatory response is a key process of host defense against invading pathogens. We report here that intranasal instillation of a B....

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Veröffentlicht in:	PLoS pathogens Jg. 5; H. 4; S. e1000359
Hauptverfasser:	Raymond, Benoit, Batsche, Eric, Boutillon, Florence, Wu, Yong-Zheng, Leduc, Dominique, Balloy, Viviane, Raoust, Eloïse, Muchardt, Christian, Goossens, Pierre L., Touqui, Lhousseine
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States Public Library of Science 01.04.2009 Public Library of Science (PLoS)
Schlagworte:	Animals Anthrax Antigens, Bacterial Antigens, Bacterial - physiology Antigens, Bacterial - toxicity Bacillus anthracis Bacterial Toxins Bacterial Toxins - toxicity Bacteriology Cell Biology/Leukocyte Signaling and Gene Expression Chromatin Chromatin - metabolism Cytokines Cytokines - genetics Cytokines - metabolism Development and progression Epigenetics Extracellular Signal-Regulated MAP Kinases Extracellular Signal-Regulated MAP Kinases - metabolism Gene Expression Gene Expression - drug effects Genetic aspects Histones Histones - metabolism Humans Immunology/Cellular Microbiology and Pathogenesis Immunology/Innate Immunity Infections Infectious Diseases/Bacterial Infections Infectious Diseases/Respiratory Infections Interleukin-8 Interleukin-8 - genetics Interleukin-8 - metabolism JNK Mitogen-Activated Protein Kinases JNK Mitogen-Activated Protein Kinases - metabolism Life Sciences Lung Lung - metabolism Mice Mice, Inbred C57BL Microbiology and Parasitology Molecular Biology/Histone Modification Mortality NF-kappa B NF-kappa B - metabolism p38 Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases - metabolism Phosphorylation Physiological aspects Pneumonia Promoter Regions, Genetic Recruitment Respiratory Mucosa Respiratory Mucosa - metabolism France
ISSN:	1553-7374, 1553-7366, 1553-7374
Online-Zugang:	Volltext
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Zusammenfassung:	Lethal toxin (LT) is a critical virulence factor of Bacillus anthracis, the etiological agent of anthrax, whose pulmonary form is fatal in the absence of treatment. Inflammatory response is a key process of host defense against invading pathogens. We report here that intranasal instillation of a B. anthracis strain bearing inactive LT stimulates cytokine production and polymorphonuclear (PMN) neutrophils recruitment in lungs. These responses are repressed by a prior instillation of an LT preparation. In contrast, instillation of a B. anthracis strain expressing active LT represses lung inflammation. The inhibitory effects of LT on cytokine production are also observed in vitro using mouse and human pulmonary epithelial cells. These effects are associated with an alteration of ERK and p38-MAPK phosphorylation, but not JNK phosphorylation. We demonstrate that although NF-kappaB is essential for IL-8 expression, LT downregulates this expression without interfering with NF-kappaB activation in epithelial cells. Histone modifications are known to induce chromatin remodelling, thereby enhancing NF-kappaB binding on promoters of a subset of genes involved in immune response. We show that LT selectively prevents histone H3 phosphorylation at Ser 10 and recruitment of the p65 subunit of NF-kappaB at the IL-8 and KC promoters. Our results suggest that B. anthracis represses the immune response, in part by altering chromatin accessibility of IL-8 promoter to NF-kappaB in epithelial cells. This epigenetic reprogramming, in addition to previously reported effects of LT, may represent an efficient strategy used by B. anthracis for invading the host.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: BR EB CM PLG LT. Performed the experiments: BR EB FB YZW DL VB ER. Analyzed the data: BR EB FB YZW DL VB CM PLG LT. Contributed reagents/materials/analysis tools: ER PLG. Wrote the paper: BR CM PLG LT.
ISSN:	1553-7374 1553-7366 1553-7374
DOI:	10.1371/journal.ppat.1000359