In:
Journal of Innate Immunity, S. Karger AG, Vol. 1, No. 5 ( 2009), p. 494-506
Abstract:
〈 i 〉 Bacillus anthracis 〈 /i 〉 is a National Institute of Allergy and Infectious Diseases Category A priority pathogen and the causative agent of the deadly disease anthrax. We applied a transposon mutagenesis system to screen for novel chromosomally encoded 〈 i 〉 B. anthracis 〈 /i 〉 virulence factors. This approach identified ClpX, the regulatory ATPase subunit of the ClpXP protease, as essential for both the hemolytic and proteolytic phenotypes surrounding colonies of 〈 i 〉 B. anthracis 〈 /i 〉 grown on blood or casein agar media, respectively. Deletion of 〈 i 〉 clpX 〈 /i 〉 attenuated lethality of 〈 i 〉 B. anthracis 〈 /i 〉 Sterne in murine subcutaneous and inhalation infection models, and markedly reduced in vivo survival of the fully virulent 〈 i 〉 B. anthracis 〈 /i 〉 Ames upon intraperitoneal challenge in guinea pigs. The extracellular proteolytic activity dependent upon ClpX function was linked to degradation of cathelicidin antimicrobial peptides, a front-line effector of innate host defense. 〈 i 〉 B. anthracis 〈 /i 〉 lacking ClpX were rapidly killed by cathelicidin and α-defensin antimicrobial peptides and lysozyme in vitro. In turn, mice lacking cathelicidin proved hyper-susceptible to lethal infection with wild-type 〈 i 〉 B. anthracis 〈 /i 〉 Sterne, confirming cathelicidin to be a critical element of innate defense against the pathogen. We conclude that ClpX is an important factor allowing 〈 i 〉 B. anthracis 〈 /i 〉 to subvert host immune clearance mechanisms, and thus represents a novel therapeutic target for prevention or therapy of anthrax, a foremost biodefense concern.
Type of Medium:
Online Resource
ISSN:
1662-811X
,
1662-8128
Language:
English
Publisher:
S. Karger AG
Publication Date:
2009
detail.hit.zdb_id:
2455818-7
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