ClpX Contributes to Innate Defense Peptide Resistance and Virulence Phenotypes of Bacillus anthracis
Open Access
- 18 June 2009
- journal article
- research article
- Published by S. Karger AG in Journal of Innate Immunity
- Vol. 1 (5), 494-506
- https://doi.org/10.1159/000225955
Abstract
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.Keywords
This publication has 38 references indexed in Scilit:
- Cathelicidin Administration Protects Mice from Bacillus anthracis Spore ChallengePublished by The American Association of Immunologists ,2008
- Clp ATPases and ClpP proteolytic complexes regulate vital biological processes in low GC, Gram‐positive bacteriaMolecular Microbiology, 2007
- Induction of the Antimicrobial Peptide CRAMP in the Blood-Brain Barrier and Meninges after Meningococcal InfectionInfection and Immunity, 2006
- Transcriptional Profiling of the Bacillus anthracis Life Cycle In Vitro and an Implied Model for Regulation of Spore FormationJournal of Bacteriology, 2006
- Proteolytic Degradation of Human Antimicrobial Peptide LL-37 by Bacillus anthracis May Contribute to VirulenceAntimicrobial Agents and Chemotherapy, 2006
- The solute‐binding component of a putative Mn(II) ABC transporter (MntA) is a novel Bacillus anthracis virulence determinantMolecular Microbiology, 2005
- Mouse Cathelin-Related Antimicrobial Peptide Chemoattracts Leukocytes Using Formyl Peptide Receptor-Like 1/Mouse Formyl Peptide Receptor-Like 2 as the Receptor and Acts as an Immune AdjuvantPublished by The American Association of Immunologists ,2005
- Effective antiprotease-antibiotic treatment of experimental anthraxBMC Infectious Diseases, 2005
- The genome sequence of Bacillus anthracis Ames and comparison to closely related bacteriaNature, 2003
- The ClpX heat-shock protein of Escherichia coli, the ATP-dependent substrate specificity component of the ClpP-ClpX protease, is a novel molecular chaperone.1995