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Bacillus anthracis HssRS signalling to HrtAB regulates haem resistance during infection.

ABSTRACT: Bacillus anthracis proliferates to high levels within vertebrate tissues during the pathogenesis of anthrax. This growth is facilitated by the acquisition of nutrient iron from host haem. However, haem acquisition can lead to the accumulation of toxic amounts of haem within B. anthracis. Here, we show that B. anthracis resists haem toxicity by sensing haem through the HssRS two-component system, which regulates expression of the haem-detoxifying transporter HrtAB. In addition, we demonstrate that B. anthracis exhibits elevated HssRS function compared with its evolutionary relative Staphylococcus aureus. Elevated haem sensing is likely required by B. anthracis due to the significant haem sensitivity exhibited by members of the genus Bacilli. We also demonstrate that B. anthracis depends on conserved residues within the previously uncharacterized sensing domain of the histidine kinase HssS for HssS function. Finally, we show that the haem- and HssRS-regulated hrtAB promoter is activated in a murine model of anthrax. These results demonstrate the evolutionary conservation of haem sensing among multiple Gram-positive bacteria and begin to provide a mechanistic explanation for the haem resistance of B. anthracis. Further, these data suggest that haem stress is experienced by bacterial pathogens during infection.

SUBMITTER: Stauff DL

PROVIDER: S-EPMC2891670 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Bacillus anthracis HssRS signalling to HrtAB regulates haem resistance during infection.

Stauff Devin L DL Skaar Eric P EP

Molecular microbiology 20090501 3

Bacillus anthracis proliferates to high levels within vertebrate tissues during the pathogenesis of anthrax. This growth is facilitated by the acquisition of nutrient iron from host haem. However, haem acquisition can lead to the accumulation of toxic amounts of haem within B. anthracis. Here, we show that B. anthracis resists haem toxicity by sensing haem through the HssRS two-component system, which regulates expression of the haem-detoxifying transporter HrtAB. In addition, we demonstrate tha ...[more]

PMID: 19400785

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Project description:The high-consequence pathogen Bacillus anthracis causes human anthrax and often results in lethal infections without the rapid administration of effective antimicrobial treatment. Antimicrobial resistance profiling is therefore critical to inform post-exposure prophylaxis and treatment decisions, especially during emergencies such as outbreaks or where intentional release is suspected. Whole-genome sequencing using a rapid long-read sequencer can uncover antimicrobial resistance patterns if genetic markers of resistance are known. To identify genomic markers associated with antimicrobial resistance, we isolated B. anthracis derived from the avirulent Sterne strain with elevated minimal inhibitory concentrations to clarithromycin. Mutants were characterized both phenotypically through broth microdilution susceptibility testing and observations during culturing, as well as genotypically with whole-genome sequencing. We identified two different in-frame insertions in the L22 ribosomal protein-encoding gene rplV, which were subsequently confirmed to be involved in clarithromycin resistance through the reversion of the mutant gene to the parent (drug-susceptible) sequence. Detection of the rplV insertions was possible with rapid long-read sequencing, with a time-to-answer within 3 h. The mutations associated with clarithromycin resistance described here will be used in conjunction with known genetic markers of resistance for other antimicrobials to strengthen the prediction of antimicrobial resistance in B. anthracis.IMPORTANCEThe disease anthrax, caused by the pathogen Bacillus anthracis, is extremely deadly if not treated quickly and appropriately. Clarithromycin is an antibiotic recommended for the treatment and post-exposure prophylaxis of anthrax by the Centers for Disease Control and Prevention; however, little is known about the ability of B. anthracis to develop resistance to clarithromycin or the mechanism of that resistance. The characterization of clarithromycin-resistant isolates presented here provides valuable information for researchers and clinicians in the event of a release of the resistant strain. Additionally, knowledge of the genetic basis of resistance provides a foundation for susceptibility prediction through rapid genome sequencing to inform timely treatment decisions.

Dataset Information

Bacillus anthracis HssRS signalling to HrtAB regulates haem resistance during infection.

Publications

Bacillus anthracis HssRS signalling to HrtAB regulates haem resistance during infection.

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