Defining the Strain-Dependent Impact of the Staphylococcal Accessory Regulator (
            <i>sarA</i>
            ) on the Alpha-Toxin Phenotype of Staphylococcus aureus

Zielińska, Agnieszka; Beenken, Karen E.; Joo, Hwang-Soo; Mrak, Lara N.; Griffin, Linda M.; Luong, Thanh T.; Lee, Chia Y.; Otto, Michael; Shaw, Lindsey N.; Smeltzer, Mark S.

doi:10.1128/jb.01517-10

Cited by 79 publications

(116 citation statements)

References 46 publications

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“…We also confirmed that the increased production of extracellular proteases plays an important role in defining the biofilm-deficient phenotype of sarA mutants (14,16,17,23,24). Moreover, we demonstrated that sarA mutants exhibit reduced virulence in a murine bacteremia model and that this can also be correlated with the increased production of extracellular proteases owing to the decreased accumulation of specific virulence factors, including alpha toxin and phenol-soluble modulins (23,25). This suggests …”

supporting

confidence: 68%

“…Mutant genes generated in the plasmid-cured JE2 derivative of strain LAC (27) were obtained from the Nebraska Transposon Mutant Library (NTML) through BEI Resources (Manassas, VA; http://www.beiresources.org). The xerC mutation was subsequently moved into strains LAC and UAMS-1 and their isogenic sarA mutants via phage-mediated transduction (25). The derivative of LAC that we employed was cured of its plasmid conferring resistance to erythromycin (33), thus allowing erythromycin selection of transductants in both the LAC and UAMS-1 recipients.…”

Section: Methodsmentioning

confidence: 99%

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XerC Contributes to Diverse Forms of Staphylococcus aureus Infection via agr -Dependent and agr -Independent Pathways

et al. 2016

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We demonstrate that mutation of xerC, which reportedly encodes a homologue of an Escherichia coli recombinase, limits biofilm formation in the methicillin-resistant Staphylococcus aureus strain LAC and the methicillin-sensitive strain UAMS-1. This was not due to the decreased production of the polysaccharide intracellular adhesin (PIA) in either strain because the amount of PIA was increased in a UAMS-1 xerC mutant and undetectable in both LAC and its isogenic xerC mutant. Mutation of xerC also resulted in the increased production of extracellular proteases and nucleases in both LAC and UAMS-1, and limiting the production of either class of enzymes increased biofilm formation in the isogenic xerC mutants. More importantly, the limited capacity to form a biofilm was correlated with increased antibiotic susceptibility in both strains in the context of an established biofilm in vivo. Mutation of xerC also attenuated virulence in a murine bacteremia model, as assessed on the basis of the bacterial loads in internal organs and overall lethality. It also resulted in the decreased accumulation of alpha toxin and the increased accumulation of protein A. These findings suggest that xerC may impact the functional status of agr. This was confirmed by demonstrating the reduced accumulation of RNAIII and AgrA in LAC and UAMS-1 xerC mutants. However, this cannot account for the biofilmdeficient phenotype of xerC mutants because mutation of agr did not limit biofilm formation in either strain. These results demonstrate that xerC contributes to biofilm-associated infections and acute bacteremia and that this is likely due to agr-independent and -dependent pathways, respectively. Staphylococcus aureus is a ubiquitous human pathogen capable of causing a wide variety of infections. These range from acute infections like bacteremia to chronic biofilm-associated infections. It is generally assumed that severe, acute infections are defined by the production of extracellular toxins, but a recent report demonstrated a negative correlation between toxicity for mammalian cells and invasive disease among human isolates (1). Although expression of the accessory gene regulator (agr), which is a primary determinant of toxin production (2), is negatively correlated with biofilm formation (3, 4), no correlation between toxicity and biofilm formation was observed in the current study. In fact, the only correlation was that decreased toxicity was associated with increased fitness, as assessed on the basis of survival in human serum (1).Nevertheless, it is clear that S. aureus has the capacity to cause diverse forms of infection. In the case of acute infections, the primary therapeutic concern is acquired resistance and the decreasing availability of effective antibiotics (5). In the case of biofilmassociated infections, a critical concern is the biofilm itself, which confers a therapeutically relevant level of intrinsic resistance to both host defenses and conventional antibiotics (6-9). There are multiple reasons for this, including the limited...

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confidence: 68%

Section: Methodsmentioning

confidence: 99%

XerC Contributes to Diverse Forms of Staphylococcus aureus Infection via agr -Dependent and agr -Independent Pathways

et al. 2016

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“…In S. aureus, strain-dependent differences in the regulation of virulence determinant biosynthesis have been reported (4,49). To determine whether the effect of RpiR inactivation on RNAIII transcription was common to S. aureus strains from divergent genetic backgrounds, the rpiRB and rpiRC mutations were transduced into S. aureus strain SA564 (38), and Northern blot analysis of RNAIII was performed (see Fig.…”

Section: Resultsmentioning

confidence: 99%

RpiR Homologues May Link Staphylococcus aureus RNAIII Synthesis and Pentose Phosphate Pathway Regulation

et al. 2011

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Staphylococcus aureus is a medically important pathogen that synthesizes a wide range of virulence determinants. The synthesis of many staphylococcal virulence determinants is regulated in part by stress-induced changes in the activity of the tricarboxylic acid (TCA) cycle. One metabolic change associated with TCA cycle stress is an increased concentration of ribose, leading us to hypothesize that a pentose phosphate pathway (PPP)-responsive regulator mediates some of the TCA cycle-dependent regulatory effects. Using bioinformatics, we identified three potential ribose-responsive regulators that belong to the RpiR family of transcriptional regulators. To determine whether these RpiR homologues affect PPP activity and virulence determinant synthesis, the rpiR homologues were inactivated, and the effects on PPP activity and virulence factor synthesis were assessed. Two of the three homologues (RpiRB and RpiRC) positively influence the transcription of the PPP genes rpiA and zwf, while the third homologue (RpiRA) is slightly antagonistic to the other homologues. In addition, inactivation of RpiRC altered the temporal transcription of RNAIII, the effector molecule of the agr quorum-sensing system. These data confirm the close linkage of central metabolism and virulence determinant synthesis, and they establish a metabolic override for quorum-sensing-dependent regulation of RNAIII transcription.Staphylococcus aureus is an important human and animal pathogen that is capable of infecting nearly all host anatomic sites. The pathogenicity of S. aureus depends on its ability to synthesize virulence factors that facilitate colonization, immune evasion, and nutrient acquisition. Virulence factor synthesis is controlled by a complex network of regulatory proteins, including the agr quorum-sensing system and the SarA family of regulators (6,29). In addition, tricarboxylic acid (TCA) cycle activity is important for the regulation of staphylococcal virulence factor synthesis (33,(39)(40)(41)48). Since the two most common types of regulation are genetic regulation and metabolic regulation, TCA cycle-dependent regulation most likely occurs via one or both of these mechanisms. Genetic regulation occurs through the repression or induction of enzyme synthesis, while metabolic regulation controls enzyme activity through the availability of substrates and cofactors. An example of staphylococcal metabolic regulation is the synthesis of capsular polysaccharide, which is regulated by TCA cycle activity through the supply of phosphoenolpyruvate for gluconeogenesis (33). Other virulence factors, such as polysaccharide intercellular adhesin (PIA), are genetically regulated by TCA cycle activity through transcriptional repression of the operon encoding the enzymes of PIA biosynthesis (i.e., icaADBC) (34,44). This TCA cycle-dependent genetic regulation likely depends on response regulators that react to metabolic changes associated with TCA cycle activity fluctuations (35,41).In Staphylococcus epidermidis, TCA cycle stress (i.e., any environm...

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“…Previous studies have revealed that a main difference between strain Newman and other S. aureus strains is the hyperactivity of the Sae TCS due to the L18P amino acid substitution in SaeS This substitution leads to the constitutive phosphorylation and activation of SaeR (1,4,18) and a series of Newman-specific phenotypes (31,32,48,58). To determine if the Sae TCS is involved in the overproduction of Ssls exhibited by strain Newman, we generated an isogenic sae-QRS mutant and examined the abundance of Ssls produced by this strain.…”

Section: Overproduction Of Rot In Clinical Isolates Is Not Sufficientmentioning

confidence: 99%

“…Interestingly, the S. aureus strain Newman, a highly virulent and commonly used methicillin-sensitive strain, exhibits high sae expression levels, due to a single amino acid substitution in the first N-terminal transmembrane domain of SaeS that results in the change of a leucine at position 18 to proline (1,4,18,48). This L18P amino acid substitution results in constitutive activation of the Sae TCS, which in turn is responsible for the altered phenotypes exhibited by strain Newman (31,58), including the increased production of exoproteins observed in this strain (1,18,31,32,48).…”

mentioning

confidence: 99%

Rot and SaeRS Cooperate To Activate Expression of the Staphylococcal Superantigen-Like Exoproteins

et al. 2012

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Staphylococcus aureus is a significant human pathogen that is capable of infecting a wide range of host tissues. This bacterium is able to evade the host immune response by utilizing a repertoire of virulence factors. These factors are tightly regulated by various two-component systems (TCS) and transcription factors. Previous studies have suggested that transcriptional regulation of a subset of immunomodulators, known as the staphylococcal superantigen-like proteins (Ssls), is mediated by the master regulators accessory gene regulator (Agr) TCS, S. aureus exoprotein expression (Sae) TCS, and Rot. Here we demonstrate that Rot and SaeR, the response regulator of the Sae TCS, synergize to coordinate the activation of the ssl promoters. We have determined that both transcription factors are required, but that neither is sufficient, for promoter activation. This regulatory scheme is mediated by direct binding of both transcription factors to the ssl promoters. We also demonstrate that clinically relevant methicillinresistant S. aureus (MRSA) strains respond to neutrophils via the Sae TCS to upregulate the expression of ssls. Until now, Rot and the Sae TCS have been proposed to work in opposition of one another on their target genes. This is the first example of these two regulators working in concert to activate promoters.

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Defining the Strain-Dependent Impact of the Staphylococcal Accessory Regulator ( sarA ) on the Alpha-Toxin Phenotype of Staphylococcus aureus

Cited by 79 publications

References 46 publications

XerC Contributes to Diverse Forms of Staphylococcus aureus Infection via agr -Dependent and agr -Independent Pathways

XerC Contributes to Diverse Forms of Staphylococcus aureus Infection via agr -Dependent and agr -Independent Pathways

RpiR Homologues May Link Staphylococcus aureus RNAIII Synthesis and Pentose Phosphate Pathway Regulation

Rot and SaeRS Cooperate To Activate Expression of the Staphylococcal Superantigen-Like Exoproteins

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