Relevance of the two-component sensor protein CiaH to acid and oxidative stress responses in Streptococcus pyogenes

Tatsuno, Ichiro; Isaka, Masanori; Okada, Ryo; Zhang, Yan; Hasegawa, Tadao

doi:10.1186/1756-0500-7-189

Cited by 23 publications

(21 citation statements)

References 41 publications

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“…Similarly, the stress response genes ciaHR, nrdR, and spxA2 and the arginine deiminase pathway genes arcABCD had significantly increased transcript levels in the ΔrocA M28 mutant strain ( Fig. 4) (44,48,61,74,75). Consistent with the RNA-seq data, the isogenic ΔrocA strain had increased resistance to acidic stress, a condition encountered in purulent lesions (70)(71)(72).…”

Section: Discussionsupporting

confidence: 58%

“…During infection, GAS cells are exposed to oxidative and acid stress in purulent lesions (70)(71)(72). Among the 41 transcription regulators that are directly or indirectly regulated by RocA in M28 GAS, 4 are implicated in oxidative and acidic stress responses, including the CiaHR twocomponent system, NrdR, and SpxA2 (Table 1) (44,48,61). Additionally, the arcABCD operon had significantly increased transcript levels in the ΔrocA mutant strain ( Fig.…”

Section: Roca Directly or Indirectly Regulates Transcription Regulatomentioning

confidence: 99%

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RocA Has Serotype-Specific Gene Regulatory and Pathogenesis Activities in Serotype M28 Group A Streptococcus

et al. 2018

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Serotype M28 group A streptococcus (GAS) is a common cause of infections such as pharyngitis ("strep throat") and necrotizing fasciitis ("flesh-eating" disease). Relatively little is known about the molecular mechanisms underpinning M28 GAS pathogenesis. Whole-genome sequencing studies of M28 GAS strains recovered from patients with invasive infections found an unexpectedly high number of missense (amino acid-changing) and nonsense (protein-truncating) polymorphisms in (egulator fov), leading us to hypothesize that altered RocA activity contributes to M28 GAS molecular pathogenesis. To test this hypothesis, an isogenic deletion mutant strain was created. Transcriptome sequencing (RNA-seq) analysis revealed that RocA inactivation significantly alters the level of transcripts for 427 and 323 genes at mid-exponential and early stationary growth phases, respectively, including genes for 41 transcription regulators and 21 virulence factors. In contrast, RocA transcriptomes from other GAS M protein serotypes are much smaller and include fewer transcription regulators. The mutant strain had significantly increased secreted activity of multiple virulence factors and grew to significantly higher colony counts under acid stress RocA inactivation also significantly increased GAS virulence in a mouse model of necrotizing myositis. Our results demonstrate that RocA is an important regulator of transcription regulators and virulence factors in M28 GAS and raise the possibility that naturally occurring polymorphisms in in some fashion contribute to human invasive infections caused by M28 GAS strains.

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Section: Discussionsupporting

confidence: 58%

Section: Roca Directly or Indirectly Regulates Transcription Regulatomentioning

confidence: 99%

RocA Has Serotype-Specific Gene Regulatory and Pathogenesis Activities in Serotype M28 Group A Streptococcus

et al. 2018

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“…ciaH has been reported to be involved in GAS responses to acid and oxidative stresses (80). Interestingly, a previous virulence study found that the ciaH deletion mutant was not attenuated in a mouse model of infection, but the route of inoculation was not specified (80). We used the mouse model of necrotizing myositis to test the hypothesis that deletion of ciaH significantly decreases virulence.…”

Section: Contribution Of Five New Genes To Necrotizing Myositis Virulmentioning

confidence: 99%

“…The ciaH gene encodes the histidine kinase sensor protein of the CiaHR regulator two-component system (TCS). ciaH has been reported to be involved in GAS responses to acid and oxidative stresses (80). Interestingly, a previous virulence study found that the ciaH deletion mutant was not attenuated in a mouse model of infection, but the route of inoculation was not specified (80).…”

Section: Contribution Of Five New Genes To Necrotizing Myositis Virulmentioning

confidence: 99%

New Pathogenesis Mechanisms and Translational Leads Identified by Multidimensional Analysis of Necrotizing Myositis in Primates

Kachroo

Eraso

Olsen

et al. 2020

mBio

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A fundamental goal of contemporary biomedical research is to understand the molecular basis of disease pathogenesis and exploit this information to develop targeted and more-effective therapies. Necrotizing myositis caused by the bacterial pathogen Streptococcus pyogenes is a devastating human infection with a high mortality rate and few successful therapeutic options. We used dual transcriptome sequencing (RNA-seq) to analyze the transcriptomes of S. pyogenes and host skeletal muscle recovered contemporaneously from infected nonhuman primates. The in vivo bacterial transcriptome was strikingly remodeled compared to organisms grown in vitro, with significant upregulation of genes contributing to virulence and altered regulation of metabolic genes. The transcriptome of muscle tissue from infected nonhuman primates (NHPs) differed significantly from that of mock-infected animals, due in part to substantial changes in genes contributing to inflammation and host defense processes. We discovered significant positive correlations between group A streptococcus (GAS) virulence factor transcripts and genes involved in the host immune response and inflammation. We also discovered significant correlations between the magnitude of bacterial virulence gene expression in vivo and pathogen fitness, as assessed by previously conducted genome-wide transposon-directed insertion site sequencing (TraDIS). By integrating the bacterial RNA-seq data with the fitness data generated by TraDIS, we discovered five new pathogen genes, namely, S. pyogenes 0281 (Spy0281 [dahA]), ihk-irr, slr, isp, and ciaH, that contribute to necrotizing myositis and confirmed these findings using isogenic deletion-mutant strains. Taken together, our study results provide rich new information about the molecular events occurring in severe invasive infection of primate skeletal muscle that has extensive translational research implications. IMPORTANCE Necrotizing myositis caused by Streptococcus pyogenes has high morbidity and mortality rates and relatively few successful therapeutic options. In addition, there is no licensed human S. pyogenes vaccine. To gain enhanced understanding of the molecular basis of this infection, we employed a multidimensional analysis strategy that included dual RNA-seq and other data derived from experimental infection of nonhuman primates. The data were used to target five streptococcal genes for pathogenesis research, resulting in the unambiguous demonstration that these genes contribute to pathogen-host molecular interactions in necrotizing infections. We exploited fitness data derived from a recently conducted genome-wide transposon mutagenesis study to discover significant correlation between the magnitude of bacterial virulence gene expression in vivo and pathogen fitness. Collectively, our findings have significant implications for translational research, potentially including vaccine efforts.

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“…ciaH , an another important TCS which controls about 120 genes [ 21 ] and involved in oxidative stress and acid tolerance [ 51 ] was found to be down regulated. An earlier report which demonstrated the increased aggregation pattern in srtB mutant M6 strain [ 52 ] aroused great interest in us to study the gene expression pattern of spy_125/srtB gene in SF370 which was found to be down regulated.…”

Section: Discussionmentioning

confidence: 99%

covR Mediated Antibiofilm Activity of 3-Furancarboxaldehyde Increases the Virulence of Group A Streptococcus

et al. 2015

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BackgroundGroup A streptococcus (GAS, Streptococcus pyogenes), a multi-virulent, exclusive human pathogen responsible for various invasive and non-invasive diseases possesses biofilm forming phenomenon as one of its pathogenic armaments. Recently, antibiofilm agents have gained prime importance, since inhibiting the biofilm formation is expected to reduce development of antibiotic resistance and increase their susceptibility to the host immune cells.Principal FindingsThe current study demonstrates the antibiofilm activity of 3Furancarboxaldehyde (3FCA), a floral honey derived compound, against GAS biofilm, which was divulged using crystal violet assay, light microscopy, and confocal laser scanning microscopy. The report is extended to study its effect on various aspects of GAS (morphology, virulence, aggregation) at its minimal biofilm inhibitory concentration (132μg/ml). 3FCA was found to alter the growth pattern of GAS in solid and liquid medium and increased the rate of auto-aggregation. Electron microscopy unveiled the increase in extra polymeric substances around cell. Gene expression studies showed down-regulation of covR gene, which is speculated to be the prime target for the antibiofilm activity. Increased hyaluronic acid production and down regulation of srtB gene is attributed to the enhanced rate of auto-aggregation. The virulence genes (srv, mga, luxS and hasA) were also found to be over expressed, which was manifested with the increased susceptibility of the model organism Caenorhabditis elegans to 3FCA treated GAS. The toxicity of 3FCA was ruled out with no adverse effect on C. elegans.SignificanceThough 3FCA possess antibiofilm activity against GAS, it was also found to increase the virulence of GAS. This study demonstrates that, covR mediated antibiofilm activity may increase the virulence of GAS. This also emphasizes the importance to analyse the acclimatization response and virulence of the pathogen in the presence of antibiofilm compounds prior to their clinical trials.

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Relevance of the two-component sensor protein CiaH to acid and oxidative stress responses in Streptococcus pyogenes

Cited by 23 publications

References 41 publications

RocA Has Serotype-Specific Gene Regulatory and Pathogenesis Activities in Serotype M28 Group A Streptococcus

RocA Has Serotype-Specific Gene Regulatory and Pathogenesis Activities in Serotype M28 Group A Streptococcus

New Pathogenesis Mechanisms and Translational Leads Identified by Multidimensional Analysis of Necrotizing Myositis in Primates

covR Mediated Antibiofilm Activity of 3-Furancarboxaldehyde Increases the Virulence of Group A Streptococcus

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