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ClpX Contributes to Innate Defense Peptide Resistance and Virulence Phenotypes of Bacillus anthracis

机译:ClpX有助于炭疽芽孢杆菌的天然防御肽抗性和毒力表型。

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摘要

Bacillus anthracis 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 B. anthracis 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 B. anthracis grown on blood or casein agar media, respectively. Deletion of clpX attenuated lethality of B. anthracis Sterne in murine subcutaneous and inhalation infection models, and markedly reduced in vivo survival of the fully virulent B. anthracis 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. B. anthracis 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 B. anthracis Sterne, confirming cathelicidin to be a critical element of innate defense against the pathogen. We conclude that ClpX is an important factor allowing B. anthracis to subvert host immune clearance mechanisms, and thus represents a novel therapeutic target for prevention or therapy of anthrax, a foremost biodefense concern.
机译:炭疽芽胞杆菌是美国国家过敏和传染病研究所的A类优先病原体,也是致命疾病炭疽的病原体。我们应用了转座子诱变系统来筛选新型染色体编码的炭疽芽孢杆菌致病因子。此方法确定ClpX,ClpXP蛋白酶的调节性ATP酶亚基,对于分别在血液或酪蛋白琼脂培养基上生长的炭疽芽孢杆菌菌落周围的溶血和蛋白水解表型都是必不可少的。在鼠皮下和吸入感染模型中,clpX的删除减弱了炭疽芽孢杆菌的致死性,并在豚鼠腹膜内攻击后显着降低了全毒性的炭疽芽孢杆菌的体内存活。依赖于ClpX功能的细胞外蛋白水解活性与先天宿主防御的一线效应物Cathelicidin抗菌肽的降解有关。缺乏ClpX的炭疽芽孢杆菌在体外被cathelicidin和α-defensin抗菌肽和溶菌酶迅速杀死。反过来,缺乏cathelicidin的小鼠被证明对野生型炭疽芽孢杆菌Sterne的致死性感染极易感,这证明cathelicidin是抵抗病原体的先天防御的关键要素。我们得出的结论是,ClpX是允许炭疽芽胞杆菌破坏宿主免疫清除机制的重要因素,因此代表了预防或治疗炭疽病(一种最重要的生物防御问题)的新型治疗靶标。

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