Abstract
Anthrax caused by Bacillus anthracis represents a major bioterroristic threat. B. anthracis produces lethal toxin (LeTx), a combination of lethal factor (LF) and protective antigen that plays a major role in anthrax pathogenesis. We demonstrate that human neutrophil alpha-defensins are potent inhibitors of LF. The inhibition of LF by human neutrophil protein (HNP-1) was noncompetitive. HNP-1 inhibited cleavage of a mitogen-activated protein kinase kinase and restored impaired mitogen-activated protein kinase signaling in LeTx-treated macrophages. HNP-1 rescued murine macrophages from B. anthracis-induced cytotoxicity, and in vivo treatment with HNP-1-3 protected mice against the fatal consequences of LeTx.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Bacterial
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Bacterial Toxins / antagonists & inhibitors*
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Female
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Furin / antagonists & inhibitors
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Humans
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Kinetics
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MAP Kinase Kinase 3 / metabolism
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Macrophages / drug effects*
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Macrophages / metabolism
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Matrix Metalloproteinase Inhibitors
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Mice
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Mice, Inbred BALB C
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Signal Transduction / drug effects*
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Spores, Bacterial / drug effects
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Survival Analysis
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Tetrazolium Salts
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Thiazoles
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alpha-Defensins / metabolism
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alpha-Defensins / pharmacology*
Substances
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Antigens, Bacterial
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Bacterial Toxins
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Matrix Metalloproteinase Inhibitors
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Tetrazolium Salts
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Thiazoles
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alpha-Defensins
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anthrax toxin
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human neutrophil peptide 1
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MAP Kinase Kinase 3
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Furin
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thiazolyl blue