Two Spx Regulators Modulate Stress Tolerance and Virulence in Streptococcus suis Serotype 2

Zheng, Chengkun; Xu, Jiali; Li, Jinquan; Hu, Luohong; Xia, Jiandong; Jia, Fan; Guo, Weina; Chen, Huanchun; Bei, Weicheng

doi:10.1371/journal.pone.0108197

Cited by 35 publications

(43 citation statements)

References 64 publications

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“…lactis encodes seven Spx paralogs, among which SpxB has been shown to be involved in the cell wall stress response. DNA microarray work with spx mutants confirmed the function of Spx as a major oxidative stress regulator (346,347). Streptococci harbor two bona fide Spx regulators, whereas enterococci have only one (346)(347)(348)(349).…”

Section: Treating Damaged Macromoleculesmentioning

confidence: 90%

“…In S. mutans, loss of spxA1, spxA2, or both attenuated virulence in the G. mellonella invertebrate model (346), while the ability to colonize the teeth of rats was significantly impaired in the ⌬spxA1 mutant and the double mutant but not in the ⌬spxA2 mutant (346). SpxA1 and SpxA2 were shown to modulate stress tolerance in S. suis, and loss of spxA1 or spxA2 significantly reduced the ability of S. suis to survive in pig blood and to disseminate to different tissues (347). In a rabbit model of infective endocarditis, a Streptococcus sanguinis ⌬spxA1 strain exhibited an approximately 5-fold reduction in competitiveness in a competitive index assay (348).…”

Section: Oxidative Stress and Virulencementioning

confidence: 99%

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Stress Physiology of Lactic Acid Bacteria

Papadimitriou

Alegría

Bron

et al. 2016

Microbiol Mol Biol Rev

539

404

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SUMMARYLactic acid bacteria (LAB) are important starter, commensal, or pathogenic microorganisms. The stress physiology of LAB has been studied in depth for over 2 decades, fueled mostly by the technological implications of LAB robustness in the food industry. Survival of probiotic LAB in the host and the potential relatedness of LAB virulence to their stress resilience have intensified interest in the field. Thus, a wealth of information concerning stress responses exists today for strains as diverse as starter (e.g.,Lactococcus lactis), probiotic (e.g., severalLactobacillusspp.), and pathogenic (e.g.,EnterococcusandStreptococcusspp.) LAB. Here we present the state of the art for LAB stress behavior. We describe the multitude of stresses that LAB are confronted with, and we present the experimental context used to study the stress responses of LAB, focusing on adaptation, habituation, and cross-protection as well as on self-induced multistress resistance in stationary phase, biofilms, and dormancy. We also consider stress responses at the population and single-cell levels. Subsequently, we concentrate on the stress defense mechanisms that have been reported to date, grouping them according to their direct participation in preserving cell energy, defending macromolecules, and protecting the cell envelope. Stress-induced responses of probiotic LAB and commensal/pathogenic LAB are highlighted separately due to the complexity of the peculiar multistress conditions to which these bacteria are subjected in their hosts. Induction of prophages under environmental stresses is then discussed. Finally, we present systems-based strategies to characterize the “stressome” of LAB and to engineer new food-related and probiotic LAB with improved stress tolerance.

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Section: Treating Damaged Macromoleculesmentioning

confidence: 90%

Section: Oxidative Stress and Virulencementioning

confidence: 99%

Stress Physiology of Lactic Acid Bacteria

Papadimitriou

Alegría

Bron

et al. 2016

Microbiol Mol Biol Rev

539

404

View full text Add to dashboard Cite

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“…Mounting evidence indicates that transcriptional regulation by Spx is critical for the ability of low-GC Gram-positive bacteria to cope with oxidative stress (9,11,12,15,16,22,26,(33)(34)(35)(36). However, proof of direct regulation by Spx in bacteria other than B. subtilis has been limited to the nox gene of S. mutans (26).…”

Section: Discussionmentioning

confidence: 99%

“…However, proof of direct regulation by Spx in bacteria other than B. subtilis has been limited to the nox gene of S. mutans (26). Moreover, while some species, such as Enterococcus faecalis and Streptococcus aureus, appear to encode only one copy of a bona fide Spx regulator, streptococcal species and, more recently, Bacillus anthracis were shown to encode two Spx proteins, dubbed SpxA1 and SpxA2 (11,15,33). From these studies, transcriptomic and…”

Section: Discussionmentioning

confidence: 99%

“…While the majority of work that has contributed to the understanding of Spx function has come from the model organism Bacillus subtilis, evidence is now accumulating that Spx proteins exert similar regulatory functions in bacterial pathogens, including S. mutans (9)(10)(11)(12)(13)(14)(15). Spx proteins do not have a DNA-binding domain but rather exert influence over transcription, positive or negative, by interacting with the C-terminal domain of the alpha subunit of the RNA polymerase (RNAP ␣-CTD) (16,17).…”

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confidence: 99%

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Transcription of Oxidative Stress Genes Is Directly Activated by SpxA1 and, to a Lesser Extent, by SpxA2 in Streptococcus mutans

et al. 2015

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The SpxA1 and SpxA2 (formerly SpxA and SpxB) transcriptional regulators of Streptococcus mutans are members of a highly conserved family of proteins found in Firmicutes, and they were previously shown to activate oxidative stress responses. In this study, we showed that SpxA1 exerts substantial positive regulatory influence over oxidative stress genes following exposure to H 2 O 2 , while SpxA2 appears to have a secondary regulatory role. In vitro transcription (IVT) assays using purified SpxA1 and/or SpxA2 showed that SpxA1 and, less often, SpxA2 directly activate transcription of some of the major oxidative stress genes. Addition of equimolar concentrations of SpxA1 and SpxA2 to the IVT reactions neither enhanced transcription of the tested genes nor disrupted the dominant role of SpxA1. Substitution of a conserved glycine residue (G52) present in both Spx proteins by arginine (Spx G52R ) resulted in strains that phenocopied the ⌬spx strains. Moreover, addition of purified SpxA1 G52R completely failed to activate transcription of ahpC, sodA, and tpx, further confirming that the G52 residue is critical for Spx functionality. IMPORTANCEStreptococcus mutans is a pathogen associated with the formation of dental caries in humans. Within the oral cavity, S. mutans routinely encounters oxidative stress. Our previous data revealed that two regulatory proteins, SpxA1 and SpxA2 (formerly SpxA and SpxB), bear high homology to the Spx regulator that has been characterized as a critical activator of oxidative stress genes in Bacillus subtilis. In this report, we prove that Spx proteins of S. mutans directly activate transcription of genes involved in the oxidative stress response, though SpxA1 appears to have a more dominant role than SpxA2. Therefore, the Spx regulators play a critical role in the ability of S. mutans to thrive within the oral cavity.T he oral cavity is colonized by hundreds of bacterial species, some of which contribute to overall oral health and others that are associated with disease, such as dental caries and periodontitis. Among the pathogenic oral bacteria, clinical evidence paired with in vitro and in vivo studies strongly associates Streptococcus mutans with dental caries onset and development (1, 2). For all organisms that inhabit the oral cavity, oxidative stresses are relevant threats for which defense mechanisms must be in place. Aside from the presence of hydrogen peroxide (H 2 O 2 ) in oral care products, members of the mitis group of streptococci, which cohabit the dental plaque along with S. mutans, are net producers of H 2 O 2 (3-5). Notably, there is an inverse correlation between the proportion of S. mutans and of members of the mitis group in health and disease, with high numbers of S. mutans organisms associated with disease and a high proportion of mitis streptococci associated with oral health (6, 7). Ultimately, the breakdown of H 2 O 2 into other variants of reactive oxygen species (ROS) can disturb the integrity of DNA and proteins and thereby pose a significant threat to...

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Streptococcus suis Deploys Multiple ATP‐Dependent Proteases for Heat Stress Adaptation

Liu,

Wang,

Zhang

et al. 2024

Journal of Basic Microbiology

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Streptococcus suis is an important zoonotic pathogen, causing cytokine storms of Streptococcal toxic shock‐like syndrome amongst humans after a wound infection into the bloodstream. To overcome the challenges of fever and leukocyte recruitment, invasive S. suis must deploy multiple stress responses forming a network and utilize proteases to degrade short‐lived regulatory and misfolded proteins induced by adverse stresses, thereby adapting and evading host immune responses. In this study, we found that S. suis encodes multiple ATP‐dependent proteases, including single‐chain FtsH and double‐subunit Clp protease complexes ClpAP, ClpBP, ClpCP, and ClpXP, which were activated as the fever of infected mice in vivo. The expression of genes ftsH, clpA/B/C, and clpP, but not clpX, were significantly upregulated in S. suis in response to heat stress, while were not changed notably under the treatments with several other stresses, including oxidative, acidic, and cold stimulation. FtsH and ClpP were required for S. suis survival within host blood under heat stress in vitro and in vivo. Deletion of ftsH or clpP attenuated the tolerance of S. suis to heat, oxidative and acidic stresses, and significantly impaired the bacterial survival within macrophages. Further analysis identified that repressor CtsR directly binds and controls the clpA/B/C and clpP operons and is relieved by heat stress. In summary, the deployments of multiple ATP‐dependent proteases form a flexible heat stress response network that appears to allow S. suis to fine‐tune the degradation or refolding of the misfolded proteins to maintain cellular homeostasis and optimal survival during infection.

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Two Spx Regulators Modulate Stress Tolerance and Virulence in Streptococcus suis Serotype 2

Cited by 35 publications

References 64 publications

Stress Physiology of Lactic Acid Bacteria

Stress Physiology of Lactic Acid Bacteria

Transcription of Oxidative Stress Genes Is Directly Activated by SpxA1 and, to a Lesser Extent, by SpxA2 in Streptococcus mutans

Streptococcus suis Deploys Multiple ATP‐Dependent Proteases for Heat Stress Adaptation

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