The Phosphoenolpyruvate Phosphotransferase System in Group A Streptococcus Acts To Reduce Streptolysin S Activity and Lesion Severity during Soft Tissue Infection

Gera, Kanika; Le, Tuquynh; Jamin, Rebecca; Eichenbaum, Zehava; McIver, Kevin S.

doi:10.1128/iai.01271-13

Cited by 23 publications

(50 citation statements)

References 62 publications

(75 reference statements)

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“…Our previous work showed that a PTS null mutant (Δ ptsI ) in the M1T1 GAS strain MGAS5005 resulted in an increased size and severity of lesions at the site of infection in a murine soft tissue infection model due to the early onset of expression and activity of Streptolysin S (SLS) during growth (Gera et al , 2014). However, the contribution of individual sugar-specific EII components in this link to virulence was not explored.…”

Section: Introductionmentioning

confidence: 99%

A PTS EII mutant library in Group A Streptococcus identifies a promiscuous man‐family PTS transporter influencing SLS‐mediated hemolysis

Sundar

Islam

Gera

et al. 2016

Molecular Microbiology

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Summary The group A streptococcus (GAS, Streptococcus pyogenes) is a Gram-positive human pathogen that must adapt to unique host environments in order to survive. Links between sugar metabolism and virulence have been demonstrated in GAS, where mutants in the phosphoenolpyruvate-dependent phosphotransferase system (PTS) exhibited Streptolysin S (SLS)-mediated hemolysis during exponential growth. This early onset hemolysis correlated with an increased lesion size and severity in a murine soft tissue infection model when compared to parental M1T1 MGAS5005. To identify the PTS components responsible for this phenotype, we insertionally inactivated the 14 annotated PTS EIIC-encoding genes in the GAS MGAS5005 genome and subjected this library to metabolic and hemolysis assays to functionally characterize each EIIC. We found that a few EIIs had a very limited influence on PTS sugar metabolism, whereas others were fairly promiscuous. The mannose-specific EII locus, encoded by manLMN, was expressed as a mannose-inducible operon that exhibited the most influence on PTS sugar metabolism, including mannose. Importantly, components of the mannose-specific EII also acted to prevent the early onset of SLS-mediated hemolysis. Interestingly, these roles were not identical in two different M1T1 GAS strains, highlighting the possible versatility of the PTS to adapt to strain-specific needs.

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Section: Introductionmentioning

confidence: 99%

A PTS EII mutant library in Group A Streptococcus identifies a promiscuous man‐family PTS transporter influencing SLS‐mediated hemolysis

Sundar

Islam

Gera

et al. 2016

Molecular Microbiology

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“…An alternative mechanism of CCR in bacteria is known as induction prevention, which is dependent on the sugar phosphotransferase (PTS) system and the phosphorylation state of a conserved histidine residue of the phosphocarrier protein HPr (36), which in the case of S. pyogenes is His15 (39). If the ME loci are controlled by a mechanism similar to induction prevention, then cells unable to produce phosphorylated His-HPr (PϳHis-HPr) should be unable to utilize malate.…”

Section: Me Is Necessary For S Pyogenes Malate-enhanced Growthmentioning

confidence: 99%

Streptococcus pyogenes Malate Degradation Pathway Links pH Regulation and Virulence

Paluscio

Caparon

2015

Infect Immun

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The ability of Streptococcus pyogenes to infect different niches within its human host most likely relies on its ability to utilize alternative carbon sources. In examining this question, we discovered that all sequenced S. pyogenes strains possess the genes for the malic enzyme (ME) pathway, which allows malate to be used as a supplemental carbon source for growth. ME is comprised of four genes in two adjacent operons, with the regulatory two-component MaeKR required for expression of genes encoding a malate permease (maeP) and malic enzyme (maeE). Analysis of transcription indicated that expression of maeP and maeE is induced by both malate and low pH, and induction in response to both cues is dependent on the MaeK sensor kinase. Furthermore, both maePE and maeKR are repressed by glucose, which occurs via a CcpA-independent mechanism. Additionally, malate utilization requires the PTS transporter EI enzyme (PtsI), as a PtsI -mutant fails to express the ME genes and is unable to utilize malate. Virulence of selected ME mutants was assessed in a murine model of soft tissue infection. MaeP -, MaeK -, and MaeR -mutants were attenuated for virulence, whereas a MaeE -mutant showed enhanced virulence compared to that of the wild type. Taken together, these data show that ME contributes to S. pyogenes' carbon source repertory, that malate utilization is a highly regulated process, and that a single regulator controls ME expression in response to diverse signals. Furthermore, malate uptake and utilization contribute to the adaptive pH response, and ME can influence the outcome of infection.A lthough it has a relatively small genome (approximately 1.8 Mbp), the pathogenic Gram-positive bacterium Streptococcus pyogenes has a remarkable ability to adapt to a variety of human tissues. This trait allows it to cause numerous diseases, ranging from superficial and self-limiting infections in soft tissues like the skin (impetigo) and pharynx (pharyngitis) to more problematic infections at a number of diverse anatomical sites (1). Understanding the complex regulatory interactions that allow it to adapt to these diverse environments provides a unique opportunity to gain insight into how a pathogen can efficiently employ a relatively limited genetic repertory to maximize its ability to cause disease.An important question is how S. pyogenes uses its limited metabolic potential to grow efficiently in diverse tissues. Considerable evidence has accrued to suggest that the patterns by which S. pyogenes exploits available growth substrates are intimately associated with both temporal and compartment-specific patterns of virulence gene expression (2-4). As a lactic acid bacterium, S. pyogenes relies exclusively on fermentation via the homolactic and mixedacid pathways to generate energy (5-7). However, the specific carbon sources it preferentially utilizes in different tissues, the temporal patterns with which these are consumed, and how these patterns impact regulation of virulence gene expression are not well understood.One approach to...

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“…Taken together, these data suggest that fruA is required for optimal growth on fructose and that FruA is the main fructose transporter for GAS. Since a PTS-defective mutant (⌬ptsI) of M1T1 GAS is defective for the utilization of fructose in the Biolog assay (12), there appears to be another PTS EII that is able to transport fructose to be metabolized, albeit not at the levels necessary to support GAS growth on fructose. Finally, the loss of fruA affects the utilization of other carbon sources; however, this is unsurprising, because a ⌬ptsI mutant also affects the utilization of non-PTS carbon sources through currently unknown mechanisms.…”

Section: Resultsmentioning

confidence: 99%

“…GAS disease progression is heavily dependent on the ability of GAS to coordinate its environmental cues and nutritional status with global transcriptional networks. Examples of such synchronization include the stand-alone regulator Mga, whose activity is directly affected by the PTS (7), LacD.1, the tagatose-1,6-bisphosphate aldolase that acts as an inhibitor of speB transcription (8), and CcpA and EI (ptsI), which both indirectly repress the expression of the hemolysin streptolysin S (SLS) independently (9)(10)(11)(12). These findings point to a direct link between GAS carbohydrate metabolism and virulence factor production.…”

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confidence: 92%

“…Carbohydrate metabolic profiles of wild-type (WT) 5448 and the 5448.⌬fruA mutant were determined via Biolog Omnilog (Biolog, Inc.) as previously described (12). Briefly, both the phenotype microarray 1 (PM1) and PM2A carbon panels (96-well microplates) were used, each containing 95 carbon sources and one negative control, for carbon utilization tests.…”

Section: Methodsmentioning

confidence: 99%

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ThefruRBAOperon Is Necessary for Group A Streptococcal Growth in Fructose and for Resistance to Neutrophil Killing during Growth in Whole Human Blood

et al. 2016

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c Bacterial pathogens rely on the availability of nutrients for survival in the host environment. The phosphoenolpyruvate-phosphotransferase system (PTS) is a global regulatory network connecting sugar uptake with signal transduction. Since the fructose PTS has been shown to impact virulence in several streptococci, including the human pathogen Streptococcus pyogenes (the group A Streptococcus [GAS]), we characterized its role in carbon metabolism and pathogenesis in the M1T1 strain 5448. Growth in fructose as a sole carbon source resulted in 103 genes affected transcriptionally, where the fru locus (fruRBA) was the most induced. Reverse transcriptase PCR showed that fruRBA formed an operon which was repressed by FruR in the absence of fructose, in addition to being under carbon catabolic repression. Growth assays and carbon utilization profiles revealed that although the entire fru operon was required for growth in fructose, FruA was the main transporter for fructose and also was involved in the utilization of three additional PTS sugars: cellobiose, mannitol, and N-acetyl-D-galactosamine. The inactivation of sloR, a fruA homolog that also was upregulated in the presence of fructose, failed to reveal a role as a secondary fructose transporter. Whereas the ability of both ⌬fruR and ⌬fruB mutants to survive in the presence of whole human blood or neutrophils was impaired, the phenotype was not reproduced in murine whole blood, and those mutants were not attenuated in a mouse intraperitoneal infection. Since the ⌬fruA mutant exhibited no phenotype in the human or mouse assays, we propose that FruR and FruB are important for GAS survival in a human-specific environment. Bacterial pathogenesis is intimately linked to the availability of nutrients that a pathogen encounters in the host, such as preferred carbohydrate sources for carbon and energy. This paradigm holds true for Gram-positive pathogens in the phylum Firmicutes, where low glucose availability conveys methicillin resistance in Staphylococcus aureus, promotes successful colonization in Streptococcus pneumoniae, stimulates host cell invasion in Listeria monocytogenes, and increases toxin production in Clostridium perfringens (1). These pathogens, like all bacteria, rely on global regulatory networks and dedicated sugar transporters in order to detect the presence of preferred carbon sources as a reflection of the nutrient status of the host environment. This allows for the appropriate coordination of virulence gene expression and disease manifestations in response to surrounding conditions. The phosphoenolpyruvate (PEP)-phosphotransferase system (PTS) is the main system that is utilized by bacteria for the uptake of sugar and sugar derivatives as well as for signal transduction (2). The PTS is made up of distinct proteins, including two cytosolic components, enzyme I (EI) (ptsI) and Hpr (ptsH), and several membrane-bound sugar-specific enzyme IIs (EIIs). Each EII is composed of two cytosolic components (EIIA-B), an integral membrane domain (EIIC), and, in s...

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The Phosphoenolpyruvate Phosphotransferase System in Group A Streptococcus Acts To Reduce Streptolysin S Activity and Lesion Severity during Soft Tissue Infection

Cited by 23 publications

References 62 publications

A PTS EII mutant library in Group A Streptococcus identifies a promiscuous man‐family PTS transporter influencing SLS‐mediated hemolysis

A PTS EII mutant library in Group A Streptococcus identifies a promiscuous man‐family PTS transporter influencing SLS‐mediated hemolysis

Streptococcus pyogenes Malate Degradation Pathway Links pH Regulation and Virulence

ThefruRBAOperon Is Necessary for Group A Streptococcal Growth in Fructose and for Resistance to Neutrophil Killing during Growth in Whole Human Blood

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