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PubMed2006

Inactivation of a two-component signal transduction system, SaeRS, eliminates adherence and attenuates virulence of Staphylococcus aureus.

Staphylococcus aureus is a major human and animal pathogen. During infection, this organism not only is able to attach to and enter host cells by using its cell surface-associated factors but also exports toxins to induce apoptosis and kill invaded cells. In this study, we identified the regulon of a two-component signal transduction system, SaeRS, and demonstrated that the SaeRS system is required for S. aureus to cause infection both in vitro and in vivo. Using microarray and real-time reverse transcriptase PCR analyses, we found that SaeRS regulates the expression of genes involved in adhesion and invasion (such as those encoding fibronectin-binding proteins and fibrinogen-binding proteins) and genes encoding alpha-, beta-, and gamma-hemolysins. Surprisingly, we found that SaeRS represses the Agr regulatory system since the mutation of saeS up-regulates agrA expression, which was confirmed by using an agr promoter-reporter fusion system. More importantly, we demonstrated that inactivation of the SaeRS system significantly decreases the bacterium-induced apoptosis and/or death of lung epithelial cells (A549) and attenuates virulence in a murine infection model. Moreover, we found that inactivation of the SaeRS system eliminates staphylococcal adhesion and internalization of lung epithelial cells. We also found that both a novel hypothetical protein (the SA1000 protein) and a bifunctional protein (Efb), which binds to extracellular fibrinogen and complement factor C3, might partially contribute to bacterial adhesion to and invasion of epithelial cells. Our results indicate that activation of the SaeRS system may be required for S. aureus to adhere to and invade epithelial cells.

Animals↗
PubMed1986

Collagen binding to Staphylococcus aureus.

Staphylococcus aureus can bind soluble collagen in a specific, saturable manner. We have previously shown that some variability exists in the degree of collagen binding between different strains of heat-killed, formaldehyde-fixed S. aureus which are commercially available as immunologic reagents. The present study demonstrates that live S. aureus of the Cowan 1 strain binds amounts of collagen per organism equivalent to those demonstrated previously in heat-killed, formaldehyde-fixed bacteria but has an affinity over 100 times greater, with Kd values of 9.7 X 10(-11) M and 4.3 X 10(-8) M for live and heat-killed organisms, respectively. Studies were also carried out with S. aureus killed by ionizing radiation, since this method of killing the organism seemed less likely to alter the binding moieties on the surface than did heat killing. Bacteria killed by exposure to gamma radiation bound collagen in a manner essentially indistinguishable from that of live organisms. Binding of collagen to irradiated cells of the Cowan 1 strain was rapid, with equilibrium reached by 30 min at 22 degrees C, and was fully reversible. The binding was not inhibited by fibronectin, fibrinogen, C1q, or immunoglobulin G, suggesting a binding site for collagen distinct from those for these proteins. Collagen binding was virtually eliminated in trypsin-treated organisms, indicating that the binding site has a protein component. Of four strains examined, Cowan 1 and S. aureus ATCC 25923 showed saturable, specific binding, while strains Woods and S4 showed a complete lack of binding. These results suggest that some strains of S. aureus contain high-affinity binding sites for collagen. While the number of binding sites per bacterium varied sixfold in the two collagen-binding strains, the apparent affinity was similar. The ability of S. aureus to bind collagen with high affinity may provide a mechanism for bacterial adhesion to host tissue and thereby play a role in the invasive characteristics of this organism.

Binding, Competitive↗
PubMed1998

Autoinducer of virulence as a target for vaccine and therapy against Staphylococcus aureus.

Staphylococcus aureus causes pathologies ranging from minor skin infections to life-threatening diseases. Pathogenic effects are largely due to production of bacterial toxin, which is regulated by an RNA molecule, RNAIII. The S. aureus protein called RAP (RNAIII activating protein) activates RNAIII, and a peptide called RIP (RNAIII inhibiting peptide), produced by a nonpathogenic bacteria, inhibits RNAIII. Mice vaccinated with RAP or treated with purified or synthetic RIP were protected from S. aureus pathology. Thus, these two molecules may provide useful approaches for the prevention and treatment of diseases caused by S. aureus.

Amino Acid Sequence↗
PubMed2005

Induction of vascular leakage through release of bradykinin and a novel kinin by cysteine proteinases from Staphylococcus aureus.

Staphylococcus aureus is a major pathogen of gram-positive septic shock and frequently is associated with consumption of plasma kininogen. We examined the vascular leakage (VL) activity of two cysteine proteinases that are secreted by S. aureus. Proteolytically active staphopain A (ScpA) induced VL in a bradykinin (BK) B(2)-receptor-dependent manner in guinea pig skin. This effect was augmented by staphopain B (SspB), which, by itself, had no VL activity. ScpA also produced VL activity from human plasma, apparently by acting directly on kininogens to release BK, which again was augmented significantly by SspB. Intravenous injection of ScpA into a guinea pig caused BK B(2)-receptor-dependent hypotension. ScpA and SspB together induced the release of leucyl-methionyl-lysyl-BK, a novel kinin with VL and blood pressure-lowering activities that are equivalent to BK. Collectively, these data suggest that production of BK and leucyl-methionyl-lysyl-BK by staphopains is a new mechanism of S. aureus virulence and bacterial shock. Therefore, staphopain-specific inhibitors and kinin-receptor antagonists could be used to treat this disease.

Animals↗
PubMed2003

RNA III inhibiting peptide inhibits in vivo biofilm formation by drug-resistant Staphylococcus aureus.

Staphylococcus aureus is a prevalent cause of bacterial infections associated with indwelling medical devices. RNA III inhibiting peptide (RIP) is known to inhibit S. aureus pathogenesis by disrupting quorum-sensing mechanisms. RIP was tested in the present study for its ability to inhibit S. aureus biofilm formation in a rat Dacron graft model. The activity of RIP was synergistic with those of antibiotics for the complete prevention of drug-resistant S. aureus infections.

Animals↗
PubMed1998

Reduction of surgical site infections in major surgery by elimination of nasal carriage of Staphylococcus aureus.

Staphylococcus aureus has long been recognized as an important pathogen in human disease. Staphylococcal infections occur regularly in hospital patients and, despite antibiotic therapy, have severe consequences. An increasing number of such infections are caused by methicillin-resistant S. aureus (MRSA) strains, many of which have become multi-resistant to treatment. In an unblinded intervention trial, with historical controls, perioperative nasal carriage of S. aureus was eliminated using mupirocin nasal ointment. A significant reduction in surgical site infection was observed post-intervention in the treated group of patients. No resistant to mupirocin was observed. The results of this study warrant a prospective randomized, placebo-controlled study to confirm the efficacy of mupirocin.

Carrier State↗
PubMed1995

Autocrine regulation of toxin synthesis by Staphylococcus aureus.

Staphylococcus aureus is a major human pathogen causing diseases which range from minor skin infection to endocarditis and toxic shock syndrome. The pathogenesis of S. aureus is due primarily to the production of toxic exoproteins, whose synthesis is controlled by a global regulatory system, agr. We show here that agr is autoinduced by a proteinaceous factor produced and secreted by the bacteria and that it is inhibited by a peptide produced by an exoprotein-deficient S. aureus mutant strain. The inhibitor, RIP, competes with the activator, RAP, and may be a mutational derivative. Our results suggest two possible approaches, independent of antibiotics, to the control of S. aureus infections. RIP may prove useful as a direct inhibitor of virulence and RAP as a vaccine against the expression of agr-induced virulence factors; either could interfere with the ability of the bacteria to establish and maintain an infection.

Bacterial Proteins↗
PubMed1996

The prospects for developing a vaccine against Staphylococcus aureus.

Staphylococcus aureus is an important bacterial pathogen with multiple virulence factors. The prevalence of antibiotic resistance among clinical isolates means that new vaccine strategies to prevent staphylococcal infections are needed. An ideal vaccine would induce antibodies to prevent bacterial adherence, promote opsonophagocytic killing by leukocytes and neutralize toxic secreted proteins.

Animals↗
PubMed1998

Surface protein adhesins of Staphylococcus aureus.

Staphylococcus aureus can colonize the host to initiate infection by adhering to components of the extracellular matrix. Adherence is mediated by surface protein adhesins (MSCRAMMs). Ligand binding by these fibronectin-, fibrinogen- and collagen-binding proteins occurs by distinct mechanisms that are being investigated at the molecular level.

Adhesins, Bacterial↗
PubMed1988

Degradation of elastin by a cysteine proteinase from Staphylococcus aureus.

Staphylococcus aureus is known to produce three very active extracellular proteinases. One of these enzymes, a cysteine proteinase, after purification to homogeneity was found to degrade insoluble bovine lung elastin at a rate comparable to human neutrophil elastase. This enzyme had no detectable activity against a range of synthetic substrates normally utilized by elastase, chymotrypsin, or trypsin-like proteinases. However, it did hydrolyze the synthetic substrate carbobenzoxy-phenylalanyl-leucyl-glutamyl-p-nitroanilide (Km = 0.5 mM, kcat = 0.16 s-1). The proteolytic activity of the cysteine proteinase was rapidly and efficiently inhibited by alpha 2-macroglobulin and also by the cysteine-specific inhibitor rat T-kininogen (Ki = 5.2 X 10(-7) M). Human kininogens, however, did not inhibit. Human plasma apparently contains other inhibitors of this enzyme, since plasma depleted of alpha 2-macroglobulin retained significant inhibitory capacity. The elastolytic activity of this S. aureus proteinase and its lack of control by human kininogens or cystatin C may explain some of the connective tissue destruction seen in bacterial infections due to this and related organisms such as may occur in septicemia, septic arthritis, and otitis.

Animals↗
PubMed2005

Escherichia coli modulates extraintestinal spread of Staphylococcus aureus.

Staphylococcus aureus remains one of the most frequent causes of life-threatening systemic infection in surgical and trauma patients. It is understood that S. aureus colonization predisposes to complicating infection, but extraintestinal dissemination of S. aureus from the intestinal lumen to the draining mesenteric lymph nodes has not been systematically studied. After oral inoculation with high numbers of S. aureus, otherwise normal mice had low levels of cecal S. aureus (6.7 log10/g) and the incidence of extraintestinal dissemination was 30%. As expected, parenteral Escherichia coli lipopolysaccharide (LPS) was associated with increased numbers of cecal S. aureus, but the incidence of translocation remained unchanged. Purified LPS had no effect on S. aureus internalization by cultured HT-29 enterocytes and no effect on S. aureus transmigration through confluent enterocytes. To begin to clarify the effect of alterations in cecal bacteria on S. aureus translocation, mice were orally inoculated with E. coli and S. aureus. Compared with mice inoculated with S. aureus alone, these mice had increased numbers of cecal E. coli and S. aureus, and the incidence of S. aureus translocation nearly doubled from 46% to 88%. Experiments with HT-29 enterocytes indicated that viable E. coli had no effect on S. aureus internalization, but viable E. coli was at least 40 times more potent in inducing S. aureus transmigration across confluent enterocytes compared with a corresponding amount of purified LPS. Thus, S. aureus disseminated from the intestinal tract of normal mice by a mechanism that could involve paracellular migration across the intestinal epithelial barrier.

Animals↗
PubMed2003

SarA and not sigmaB is essential for biofilm development by Staphylococcus aureus.

Staphylococcus aureus biofilm formation is associated with the production of the polysaccharide intercellular adhesin (PIA/PNAG), the product of the ica operon. The staphylococcal accessory regulator, SarA, is a central regulatory element that controls the production of S. aureus virulence factors. By screening a library of Tn917 insertions in a clinical S. aureus strain, we identified SarA as being essential for biofilm development. Non-polar mutations of sarA in four genetically unrelated S. aureus strains decreased PIA/PNAG production and completely impaired biofilm development, both in steady state and flow conditions via an agr-independent mechanism. Accordingly, real-time PCR showed that the mutation in the sarA gene resulted in downregulation of the ica operon transcription. We also demonstrated that complete deletion of sigmaB did not affect PIA/PNAG production and biofilm formation, although it slightly decreased ica operon transcription. Furthermore, the sarA-sigmaB double mutant showed a significant decrease of ica expression but an increase of PIA/PNAG production and biofilm formation compared to the sarA single mutant. We propose that SarA activates S. aureus development of biofilm by both enhancing the ica operon transcription and suppressing the transcription of either a protein involved in the turnover of PIA/PNAG or a repressor of its synthesis, whose expression would be sigmaB-dependent.

Bacterial Proteins↗
PubMed1979

[Action of methicillin on the synthesis of surface protein A and type antigen 18 in Staphylococcus aureus].

Staphylococcus aureus methicillin resistants strains cultivated on subinhibiting methicillin concentrations are not modified as concern protein A and type antigen 18. Low protein A production of these resistant strains known to be heterogenous as concern their resistance to methicillin does not correspond to absence of protein A on the highly resistant fraction of the population.

Antigens, Bacterial↗
PubMed2004

Genetic characterization of staphopain genes in Staphylococcus aureus.

Staphylococcus aureus , a leading cause of bacterial infections in humans, is endowed with a wealth of virulence factors that contribute to the disease process. Several extracellular proteolytic enzymes, including cysteine proteinases referred to as the staphopains (staphopain A, encoded by the scpA gene, and staphopain B, encoded by sspB ), have proposed roles for staphylococcal virulence. Here we present data regarding the distribution, copy number and genetic variability of the genes encoding the staphopains in a large number of S. aureus strains. The polymorphism of the scpA and sspB genes in three laboratory strains and 126 clinical isolates was analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Both genes were detected in all isolates by PCR amplification and, based on the PCR-RFLP patterns, classified as four types for scpA and six types for sspB . Those with the most divergent patterns were subjected to DNA sequencing and compared with genomic sequence data for the seven available strains of S. aureus . Southern blot analysis of the scpA and sspB sequences indicates that they are strongly conserved as single-copy genes in the genome of each S. aureus strain investigated. Taken together, these data suggest that the staphopains have important housekeeping and/or virulence functions, and therefore may constitute an interesting target for the development of therapeutic inhibitors for the treatment of staphylococcal diseases.

Amino Acid Sequence↗
PubMed1985

Use of resistant mutants to study the interaction of triton X-100 with Staphylococcus aureus.

Staphylococcus aureus mutants resistant to the nonionic detergent Triton X-100, isolated from the wild-type strain H and the autolysin-deficient strain RUS3, could grow and divide in broth containing 5% (vol/vol) Triton X-100, while growth of the parental strains was markedly inhibited above the critical micellar concentration (0.02%) of the detergent. Growth-inhibitory concentrations of Triton X-100 killed wild-type cells without demonstrable cellular lysis. Triton X-100 stimulated autolysin activity of S. aureus cells under nongrowing conditions, and this lytic response was markedly reduced in energy-poisoned cells. In contrast, the detergent had no effect on the activity of autolysins in cell-free systems, and growth in the presence of Triton X-100 did not alter either the cellular autolysin activity or the susceptibility of cell walls to exogenous lytic enzymes. Treatment with either Triton X-100 or penicillin G in the growth medium stimulated release of predominantly acylated intracellular lipoteichoic acid and sensitized staphylococci to Triton X-100-induced autolysis. There was no significant difference in the cell wall and membrane compositions or Triton X-100 binding between the parental strains and the resistant mutants. The resistant mutant TXR1, derived from S. aureus H, had a higher level of L-alpha-glycerophosphate dehydrogenase activity, and its oxygen uptake was more resistant to inhibition by a submicellar concentration (0.008%) of Triton X-100. Growth in the presence of subinhibitory concentrations of Triton X-100 rendered S. aureus H cells phenotypically resistant to the detergent and greatly stimulated the level of oxygen uptake. Membranes isolated from such cells exhibited enhanced activity of the respiratory enzymes succinic dehydrogenase and L-alpha-glycerophosphate dehydrogenase.

Azides↗
PubMed2004

Clinical isolates of Staphylococcus intermedius masquerading as methicillin-resistant Staphylococcus aureus.

Staphylococcus intermedius is a zoonotic organism that can be associated with human disease. We report two separate cases of S. intermedius infection in which a false-positive rapid penicillin binding protein 2a latex test in conjunction with the phenotypic properties of beta-hemolysis and coagulase positivity allowed the clinical isolates to masquerade as methicillin-resistant Staphylococcus aureus. 16S rRNA gene sequencing and the absence of mecA revealed the strains to be methicillin-susceptible S. intermedius.

Adult↗