Human alpha-defensins neutralize anthrax lethal toxin and protect against its fatal consequences.
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.
Kim
Chun
C
Department of Immunology, Max Planck Institute for Infection Biology, Schumannstrasse 21-22, D-10117 Berlin, Germany.
Gajendran
Nadesan
N
Mittrücker
Hans-Willi
HW
Weiwad
Matthias
M
Song
Young-Hwa
YH
Hurwitz
Robert
R
Wilmanns
Matthias
M
Fischer
Gunter
G
Kaufmann
Stefan H E
SH
D000818:Animals; D000942:Antigens, Bacterial; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D005260:Female; D045683:Furin / Q000037:antagonists & inhibitors; D006801:Humans; D007700:Kinetics; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction / Q000187:drug effects*; D013171:Spores, Bacterial / Q000187:drug effects; D016019:Survival Analysis; D013778:Tetrazolium Salts; D013844:Thiazoles; D023084:alpha-Defensins / Q000378:metabolism / Q000494:pharmacology*
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D061965:Matrix Metalloproteinase Inhibitors; D013778:Tetrazolium Salts; D013844:Thiazoles; D023084:alpha-Defensins; C030325:anthrax toxin; C406413:human neutrophil peptide 1; D048371:MAP Kinase Kinase 3; D045683:Furin; C022616:thiazolyl blue