Abstract
We previously demonstrated that the HtrA (High Temperature Requirement A) protease/chaperone active in the quality control of protein synthesis, represents an important virulence determinant of Bacillus anthracis. Virulence attenuation of htrA-disrupted Bacillus anthracis strains was attributed to susceptibility of ΔhtrA strains to stress insults, as evidenced by affected growth under various stress conditions. Here, we report a comparative RNA-seq transcriptomic study generating a database of differentially expressed genes in the B. anthracis htrA-disrupted and wild type parental strains under oxidative stress. The study demonstrates that, apart from protease and chaperone activities, HtrA exerts a regulatory role influencing expression of more than 1000 genes under stress. Functional analysis of groups or individual genes exhibiting strain-specific modulation, evidenced (i) massive downregulation in the ΔhtrA and upregulation in the WT strains of various transcriptional regulators, (ii) downregulation of translation processes in the WT strain, and (iii) downregulation of metal ion binding functions and upregulation of sporulation-associated functions in the ΔhtrA strain. These modulated functions are extensively discussed. Fifteen genes uniquely upregulated in the wild type strain were further interrogated for their modulation in response to other stress regimens. Overexpression of one of these genes, encoding for MazG (a nucleoside triphosphate pyrophosphohydrolase involved in various stress responses in other bacteria), in the ΔhtrA strain resulted in partial alleviation of the H2O2-sensitive phenotype.
Highlights
The Gram-positive spore-forming obligate pathogen Bacillus anthracis represents the etiological agent of anthrax, a currently rare disease in humans, yet potentially associated with intentional bioterror use [1,2]
The study substantiates the important role HtrA plays in the adaptation of the bacteria to the hostile environment, and strengthens the notion that in addition to its direct role in post-translation processing and quality control of proteins associated with its chaperone and protease catalytic activities, B. anthracis HtrA exerts a pleotropic effect on gene expression under oxidative stress conditions
It was postulated that the significant virulence attenuation exhibited by the fully virulent Vollum or the acapsular Sterne strains upon abrogation of HtrA expression, may be attributed to inability to respond optimally to oxidative stress
Summary
The Gram-positive spore-forming obligate pathogen Bacillus anthracis represents the etiological agent of anthrax, a currently rare disease in humans, yet potentially associated with intentional bioterror use [1,2]. HtrA proteins are structurally and functionally conserved across a wide range of evolutionary distinct phylogenetic classes both in prokaryotes and eukaryotes [24] They exhibit the dual biological activities of chaperones and proteases, are involved in manifestation of virulence of many pathogens, and represent potential targets for therapy [25,26,27,28,29,30]. The study substantiates the important role HtrA plays in the adaptation of the bacteria to the hostile environment, and strengthens the notion that in addition to its direct role in post-translation processing and quality control of proteins associated with its chaperone and protease catalytic activities, B. anthracis HtrA exerts a pleotropic effect on gene expression under oxidative stress conditions
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