Regulatory circuits controlling Spx levels in <i>Streptococcus mutans</i>

Ganguly, Tridib; Kajfasz, Jessica K.; Abranches, Jacqueline; Lemos, José A.

doi:10.1111/mmi.14499

Cited by 18 publications

(19 citation statements)

References 77 publications

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“…Consistent with these findings are reports implicating the S. mutans PerR regulator as a repressor of dpr and sod transcription(27). In addition, a recent report describes corepression of the S. mutans spxA1 gene by the PerR and SloR metalloregulators(33). The spxA1 gene product has been previously described as a positive regulator of oxidative stress tolerance in S. mutans(33)(34)(35).…”

supporting

confidence: 58%

“…In addition, a recent report describes corepression of the S. mutans spxA1 gene by the PerR and SloR metalloregulators(33). The spxA1 gene product has been previously described as a positive regulator of oxidative stress tolerance in S. mutans(33)(34)(35). Clearly, further investigation is warranted to decipher the complexities of antioxidant gene regulation involving SpxA1.In summary, we propose that PerR is a prevalent redox sensing metalloregulator in S. mutans and that H2O2 is the possible signaling molecule that activates PerR and promotes S. mutans stress adaptation.…”

mentioning

confidence: 99%

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Regulatory involvement of the PerR and SloR metalloregulators in theStreptococcus mutansoxidative stress response

Ruxin

Schwartzman

Davidowitz

et al. 2020

Preprint

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Streptococcus mutans is a commensal of the human oral microbiome that can instigate dental caries under conditions of dysbiosis. This study investigates S. mutans metalloregulators and their involvement in mediating a response to oxidative stress. Oxidative stress in the oral cavity can derive from temporal increases in reactive oxygen species (ROS) after meal consumption, and from endogenous bacterial ROS-producers that colonize the dentition as constituents of dental plaque. We hypothesize that the PerR (SMU.593) and SloR (SMU.186) metalloregulatory proteins in S. mutans contribute to oxidative stress tolerance by regulating the expression of genes responsive to H2O2 challenge. The results of qRT-PCR experiments with S. mutans cultures exposed to 0.5mM H2O2 reveal perR transcription that is responsive to the peroxide stressor, and sloR transcription that is subject to PerR repression. The results of gel shift assays support direct binding of a PerR homolog to the S. mutans sloR promoter at Fur and PerR consensus sequences on the UA159 chromosome. In addition, transcription of the S. mutans tpx and dpr antioxidant genes is upregulated in a perR/sloR double knockout mutant, consistent with heightened resistance of the S. mutans GMS802 perR-deficient strain when challenged with H2O2. Cumulatively, these results reveal a relationship of reciprocity between the PerR and SloR metalloregulators during the S. mutans response to oxidative stress and begin to elucidate the fitness strategies that evolved to foster S. mutans survival and persistence in the transient environments of the human oral cavity.IMPORTANCEIn 2020, untreated dental caries, especially in the permanent dentition, ranked among the most prevalent infectious diseases worldwide. Moreover, caries disproportionately affects children and individuals of low socioeconomic status. Untreated caries can lead to systemic health problems and has been associated with extended school and work absences, inappropriate use of emergency departments, and an inability for military forces to deploy. In combination with public health policy, research aimed at alleviating S. mutans-induced tooth decay is important because it can improve oral health, as well as overall health, especially for underserved populations. This research is focused on the S. mutans SloR and PerR metalloregulatory proteins that can help inform the development of therapeutics aimed at alleviating and potentially preventing dental caries.

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supporting

confidence: 58%

mentioning

confidence: 99%

Regulatory involvement of the PerR and SloR metalloregulators in theStreptococcus mutansoxidative stress response

Ruxin

Schwartzman

Davidowitz

et al. 2020

Preprint

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“…Our manual searches identified four additional genes (mntH, spxA1, sodA and smu995) with putative PerR-binding boxes albeit, these additional motifs contained four mismatches from the consensus, with the exception of sodA that contained only one mismatch (Table 1). Of note, we recently showed that spxA1 is co-repressed by PerR and SloR in a redundant manner as only the simultaneous inactivation of perR and sloR increased spxA1 transcription (36). Overall, a trend was observed showing that expression levels of most of the genes tested were elevated in UA-perR and UA∆perR as compared to UA159, the iron transport systems feoAB and smu995-998 were the notable exceptions (Fig.…”

Section: Exploration Of the Regulatory Reach Ofmentioning

confidence: 81%

Increased oxidative stress tolerance of a spontaneously-occurringperRgene mutation inStreptococcus mutansUA159

Kajfasz

Zuber

Ganguly

et al. 2020

Preprint

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The ability of bacteria such as the dental pathogen Streptococcus mutans to coordinate a response against damage-inducing oxidants is a critical aspect of their pathogenicity. The oxidative stress regulator SpxA1 has been proven to be a major player in the ability of S. mutans to withstand both disulfide and peroxide stresses. While studying spontaneously-occurring variants of an S. mutans ΔspxA1 strain, we serendipitously discovered that our S. mutans UA159 host strain bore a single nucleotide deletion within the coding region ofperR, resulting in a premature truncation of the encoded protein. PerR is a metal-dependent transcriptional repressor that senses and responds to peroxide stress such that loss of PerR activity results in activation of oxidative stress responses. To determine the impact of loss of PerR regulation, we obtained a UA159 isolated bearing an intact perR copy and created a clean perR deletion mutant. Our findings indicate that loss of PerR activity results in a strain that is primed to tolerate oxidative stresses in the laboratory setting. Interestingly, RNA-Seq and targeted transcriptional expression analyses reveal that PerR has a minor contribution to the ability of S. mutans to orchestrate a transcriptional response to peroxide stress. Furthermore, we detected loss-of-function perR mutations in two other commonly used laboratory strains of S. mutans suggesting that this may be not be an uncommon occurrence. This report serves as a cautionary warning regarding the so-called domestication of laboratory strains and advocates for the implementation of more stringent strain authentication practices.ImportanceA resident of the human oral biofilm, Streptococcus mutans is one of the major bacterial pathogens associated with dental caries. This report highlights a spontaneously-occurring mutation within the laboratory strain S. mutans UA159, found in the coding region of perR, a gene encoding a transcriptional repressor associated with peroxide tolerance. Though perR mutant strains of S. mutans showed a distinct growth advantage and enhanced tolerance toward H2O2, a ΔperR deletion strain showed a small number of differentially expressed genes as compared to the parent strain, suggesting few direct regulatory targets. In addition to characterizing the role of PerR in S. mutans, our findings serve as a warning to laboratory researchers regarding bacterial adaptation to in vitro growth conditions.

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Section: Discussionmentioning

confidence: 99%

“…Subsequent PerR binding to Fur-and PerR-like consensus sequences is then enabled (27). In addition, a recent report describes corepression of the S. mutans spxA1 gene by the PerR and SloR metalloregulators (33). The spxA1 gene product has been previously described as a positive regulator of oxidative stress tolerance in S. mutans (33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

Regulatory Involvement of the PerR and SloR Metalloregulators in the Streptococcus mutans Oxidative Stress Response

et al. 2021

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Streptococcus mutans is a commensal of the human oral microbiome that can promote dental caries under conditions of dysbiosis. This study investigates metalloregulators and their involvement in the S. mutans oxidative stress response. Oxidative stress in the human mouth can derive from temporal increases in reactive oxygen species (ROS) after meal consumption and from endogenous bacterial ROS-producers that colonize the dentition. We hypothesize that the S. mutans PerR (SMU.593) and SloR (SMU.186) metalloregulatory proteins contribute to the regulation of oxidative stress genes and their products. Expression assays with S. mutans UA159 wild type cultures exposed to H2O2 reveal that H2O2 upregulates perR, and that PerR represses sloR transcription upon binding directly to Fur and PerR consensus sequences within the sloR operator. In addition, the results of Western blot experiments implicate the Clp proteolytic system in SloR degradation under conditions of H2O2-stress. To reveal a potential role for SloR in the H2O2-resistant phenotype of S. mutans GMS802 (a perR-deficient strain), we generated a sloR/perR double knockout mutant, GMS1386, where we observed upregulation of the tpx and dpr antioxidant genes. These results are consistent with GMS802 H2O2 resistance and with a role for PerR as a transcriptional repressor. Cumulatively, these findings support a reciprocal relationship between PerR and SloR during the S. mutans oxidative stress response and begin to elucidate the fitness strategies that evolved to foster S. mutans persistence in the transient environments of the human oral cavity. IMPORTANCE In 2020, untreated dental caries, especially in the permanent dentition, ranked among the most prevalent infectious diseases worldwide, disproportionately impacting individuals of low socioeconomic status. Untreated caries can lead to systemic health problems and has been associated with extended school and work absences, inappropriate use of emergency departments, and an inability for military forces to deploy. Together with public health policy, research aimed at alleviating S. mutans-induced tooth decay is important because it can improve oral health (and overall health), especially in underserved populations. This research, focused on S. mutans metalloregulatory proteins and their gene targets, is significant because it can promote virulence gene control in an important oral pathogen, and contribute to the development of an anti-caries therapeutic that can reduce tooth decay.

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Regulatory circuits controlling Spx levels in Streptococcus mutans

Cited by 18 publications

References 77 publications

Regulatory involvement of the PerR and SloR metalloregulators in theStreptococcus mutansoxidative stress response

Regulatory involvement of the PerR and SloR metalloregulators in theStreptococcus mutansoxidative stress response

Increased oxidative stress tolerance of a spontaneously-occurringperRgene mutation inStreptococcus mutansUA159

Regulatory Involvement of the PerR and SloR Metalloregulators in the Streptococcus mutans Oxidative Stress Response

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