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Streptococcus mutans SpxA2 relays the signal of cell envelope stress from LiaR to effectors that maintain cell wall and membrane homeostasis.

ABSTRACT: Streptococcus mutans is a major etiologic agent of dental caries, which is the most common chronic infectious disease worldwide. S. mutans is particularly adept at causing caries due to its exceptional capacity to form biofilms and its ability to survive acidic conditions that arrest acid production and growth in many more benign members of the oral microbiota. Two mechanisms utilized by S. mutans to tolerate acid are: modulation of the membrane fatty acid content and utilization of the F₁ F₀ -ATPase to pump protons out of the cytosol. In this study, the role of the spxA2 transcriptional regulator in these two pathways, and overall cell envelope homeostasis, was examined. Loss of spxA2 resulted in an increase in the proportion of saturated fatty acids in the S. mutans membrane and altered transcription of several genes involved in the production of these membrane fatty acids, including fabT and fabM. Furthermore, activity of the F₁ F₀ -ATPase was increased in the ∆spxA2 strain. Transcription of spxA2 was elevated in the presence of a variety of membrane stressors, and highly dependent on the liaR component of the LiaFSR system, which is known to sense cell envelope stress in many Gram-positive bacteria. Finally, deletion of ∆spxA2 led to altered susceptibility of S. mutans to membrane stressors. Overall, the results of this study indicate that spxA2 serves a crucial role in transmitting the signal of cell wall/membrane damage from the LiaFSR sensor to downstream effectors in the SpxA2 regulon which restore and maintain membrane and cell wall homeostasis.

SUBMITTER: Baker JL

PROVIDER: S-EPMC7202993 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The LiaFSR system regulates the cell envelope stress response in Streptococcus mutans.

Project description:Maintaining cell envelope integrity is critical for bacterial survival, including bacteria living in a complex and dynamic environment such as the human oral cavity. Streptococcus mutans, a major etiological agent of dental caries, uses two-component signal transduction systems (TCSTSs) to monitor and respond to various environmental stimuli. Previous studies have shown that the LiaSR TCSTS in S. mutans regulates virulence traits such as acid tolerance and biofilm formation. Although not examined in streptococci, homologs of LiaSR are widely disseminated in Firmicutes and function as part of the cell envelope stress response network. We describe here liaSR and its upstream liaF gene in the cell envelope stress tolerance of S. mutans strain UA159. Transcriptional analysis established liaSR as part of the pentacistronic liaFSR-ppiB-pnpB operon. A survey of cell envelope antimicrobials revealed that mutants deficient in one or all of the liaFSR genes were susceptible to Lipid II cycle interfering antibiotics and to chemicals that perturbed the cell membrane integrity. These compounds induced liaR transcription in a concentration-dependent manner. Notably, under bacitracin stress conditions, the LiaFSR signaling system was shown to induce transcription of several genes involved in membrane protein synthesis, peptidoglycan biosynthesis, envelope chaperone/proteases, and transcriptional regulators. In the absence of an inducer such as bacitracin, LiaF repressed LiaR-regulated expression, whereas supplementing cultures with bacitracin resulted in derepression of liaSR. While LiaF appears to be an integral component of the LiaSR signaling cascade, taken collectively, we report a novel role for LiaFSR in sensing cell envelope stress and preserving envelope integrity in S. mutans.

| S-EPMC2681809 | biostudies-literature

BrpA is involved in regulation of cell envelope stress responses in Streptococcus mutans.

Project description:Previous studies have shown that BrpA plays a major role in acid and oxidative stress tolerance and biofilm formation by Streptococcus mutans. Mutant strains lacking BrpA also display increased autolysis and decreased viability, suggesting a role for BrpA in cell envelope integrity. In this study, we examined the impact of BrpA deficiency on cell envelope stresses induced by envelope-active antimicrobials. Compared to the wild-type strain UA159, the BrpA-deficient mutant (TW14D) was significantly more susceptible to antimicrobial agents, especially lipid II inhibitors. Several genes involved in peptidoglycan synthesis were identified by DNA microarray analysis as downregulated in TW14D. Luciferase reporter gene fusion assays also revealed that expression of brpA is regulated in response to environmental conditions and stresses induced by exposure to subinhibitory concentrations of cell envelope antimicrobials. In a Galleria mellonella (wax worm) model, BrpA deficiency was shown to diminish the virulence of S. mutans OMZ175, which, unlike S. mutans UA159, efficiently kills the worms. Collectively, these results suggest that BrpA plays a role in the regulation of cell envelope integrity and that deficiency of BrpA adversely affects the fitness and diminishes the virulence of OMZ175, a highly invasive strain of S. mutans.

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The two-component response regulator LiaR regulates cell wall stress responses, pili expression and virulence in group B Streptococcus.

Project description:Group B Streptococcus (GBS) remains the leading cause of early onset sepsis among term infants. Evasion of innate immune defences is critical to neonatal GBS disease pathogenesis. Effectors of innate immunity, as well as numerous antibiotics, frequently target the peptidoglycan layer of the Gram-positive bacterial cell wall. The intramembrane-sensing histidine kinase (IM-HK) class of two-component regulatory systems has been identified as important to the Gram-positive response to cell wall stress. We have characterized the GBS homologue of LiaR, the response regulator component of the Lia system, to determine its role in GBS pathogenesis. LiaR is expressed as part of a three-gene operon (liaFSR) with a promoter located upstream of liaF. A LiaR deletion mutant is more susceptible to cell wall-active antibiotics (vancomycin and bacitracin) as well as antimicrobial peptides (polymixin B, colistin, and nisin) compared to isogenic wild-type GBS. LiaR mutant GBS are significantly attenuated in mouse models of both GBS sepsis and pneumonia. Transcriptional profiling with DNA microarray and Northern blot demonstrated that LiaR regulates expression of genes involved in microbial defence against host antimicrobial systems including genes functioning in cell wall synthesis, pili formation and cell membrane modification. We conclude that the LiaFSR system, the first member of the IM-HK regulatory systems to be studied in GBS, is involved in sensing perturbations in the integrity of the cell wall and activates a transcriptional response that is important to the pathogenesis of GBS infection.

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The Pseudomonas Quinolone Signal Inhibits Biofilm Development of Streptococcus mutans.

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| S-EPMC4462930 | biostudies-literature

The Streptococcus mutans serine/threonine kinase, PknB, regulates competence development, bacteriocin production, and cell wall metabolism.

Project description:Bacteria can detect, transmit, and react to signals from the outside world by using two-component systems (TCS) and serine-threonine kinases and phosphatases. Streptococcus mutans contains one serine-threonine kinase, encoded by pknB. A gene encoding a serine-threonine phosphatase, pppL, is located upstream of pknB. In this study, the phenotypes of pknB and pppL single mutants and a pknB pppL double mutant were characterized. All mutants exhibited a reduction in genetic transformability and biofilm formation, showed abnormal cell shapes, grew slower than the wild-type strain in several complex media, and exhibited reduced acid tolerance. The mutants had reduced cariogenic capacity but no significant defects in colonization in a rat caries model. Whole-genome transcriptome analysis revealed that a pknB mutant showed reduced expression of genes involved in bacteriocin production and genetic competence. Among the genes that were differentially regulated in the pknB mutant, several were likely to be involved in cell wall metabolism. One such gene, SMU.2146c, and two genes encoding bacteriocins were shown to also be downregulated in a vicK mutant, which encodes a sensor kinase involved in the response to oxidative stress. Collectively, the results lead us to speculate that PknB may modulate the activity of the two-component signal transduction systems VicKR and ComDE. Real-time reverse transcriptase PCR (RT-PCR) showed that genes downregulated in the pknB mutant were upregulated in the pppL mutant, indicating that PppL serves to counteract PknB.

| S-EPMC2863541 | biostudies-literature

Induction of clpP expression by cell-wall targeting antibiotics in Streptococcus mutans.

Project description:Streptococcus mutans is one of the major bacteria of the human oral cavity that is associated with dental caries. The pathogenicity of this bacterium is attributed to its ability to rapidly respond and adapt to the ever-changing conditions of the oral cavity. The major player in this adaptive response is ClpP, an intracellular protease involved in degradation of misfolded proteins during stress responses. S. mutans encodes a single clpP gene with an upstream region uniquely containing multiple tandem repeat sequences (RSs). Here, we explored expression of clpP with respect to various stresses and report some new findings. First, we found that at sub-inhibitory concentration, certain cell-wall damaging antibiotics were able to induce clpP expression. Specifically, third- and fourth-generation cephalosporins that target penicillin-binding protein 3 (PBP3) strongly enhanced the clpP expression. However, induction of clpP was weak when the first-generation cephalosporins with lower affinity to PBP3 were used. Surprisingly, carbapenems, which primarily target PBP2, induced expression of clpP the least. Second, we found that a single RS element was capable of inducing clpP expression as efficiently as with the wild-type seven RS elements. Third, we found that the RS-element-mediated modulation of clpP expression was strain dependent, suggesting that specific host factors might be involved in the transcription. And finally, we observed that ClpP regulates its own expression, as the expression of clpP-gusA was higher in a clpP-deficient mutant. This suggests that ClpP is involved in the degradation of activator(s) involved in its own transcription.

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Function-adaptive clustered nanoparticles reverse Streptococcus mutans dental biofilm and maintain microbiota balance.

Project description:Dental plaques are biofilms that cause dental caries by demineralization with acidogenic bacteria. These bacteria reside inside a protective sheath which makes any curative treatment challenging. We propose an antibiotic-free strategy to disrupt the biofilm by engineered clustered carbon dot nanoparticles that function in the acidic environment of the biofilms. In vitro and ex vivo studies on the mature biofilms of Streptococcus mutans revealed >90% biofilm inhibition associated with the contact-mediated interaction of nanoparticles with the bacterial membrane, excessive reactive oxygen species generation, and DNA fragmentation. An in vivo examination showed that these nanoparticles could effectively suppress the growth of S. mutans. Importantly, 16S rRNA analysis of the dental microbiota showed that the diversity and richness of bacterial species did not substantially change with nanoparticle treatment. Overall, this study presents a safe and effective approach to decrease the dental biofilm formation without disrupting the ecological balance of the oral cavity.

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Genes involved in cell wall localization and side chain formation of rhamnose-glucose polysaccharide in Streptococcus mutans.

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| S-EPMC107649 | biostudies-literature

Deficiency of MecA in Streptococcus mutans Causes Major Defects in Cell Envelope Biogenesis, Cell Division, and Biofilm Formation.

Project description:MecA is an adaptor protein that guides the ClpC/P-mediated proteolysis. A S. mutans MecA-deficient mutant was constructed by double-crossover allelic exchange and analyzed for the effects of such a deficiency on cell biology and biofilm formation. Unlike the wild-type, UA159, the mecA mutant, TW416, formed mucoid and smooth colonies, severely clumped in broth and had a reduced growth rate. Transmission electron microscopy analysis revealed that TW416 grows primarily in chains of giant "swollen" cells with multiple asymmetric septa, unlike the coccoid form of UA159. As compared to UA159, biofilm formation by TW416 was significantly reduced regardless of the carbohydrate sources used for growth (P < 0.001). Western blot analysis of TW416 whole cell lysates showed a reduced expression of the glucosyltransferase GtfC and GtfB, as well as the P1 and WapA adhesins providing an explanation for the defective biofilm formation of TW416. When analyzed by a colorimetric assay, the cell wall phosphate of the mutant murein sacculi was almost 20-fold lower than the parent strain (P < 0.001). Interestingly, however, when analyzed using immunoblotting of the murein sacculi preps with UA159 whole cell antiserum as a probe, TW416 was shown to possess significantly higher signal intensity as compared to the wild-type. There is also evidence that MecA in S. mutans is more than an adaptor protein, although how it modulates the bacterial pathophysiology, including cell envelope biogenesis, cell division, and biofilm formation awaits further investigation.

| S-EPMC6141683 | biostudies-literature

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