Comparative Analysis of USA300 Virulence Determinants in a Rabbit Model of Skin and Soft Tissue Infection

Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, and Bethesda, Maryland, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 09/2011; 204(6):937-41. DOI: 10.1093/infdis/jir441
Source: PubMed


Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections are frequently associated with strains harboring genes encoding Panton-Valentine leukocidin (PVL). The role of PVL in the success of the epidemic CA-MRSA strain USA300 remains unknown. Here we developed a skin and soft tissue infection model in rabbits to test the hypothesis that PVL contributes to USA300 pathogenesis and compare it with well-established virulence determinants: alpha-hemolysin (Hla), phenol-soluble modulin-alpha peptides (PSMα), and accessory gene regulator (Agr). The data indicate that Hla, PSMα, and Agr contribute to the pathogenesis of USA300 skin infections in rabbits, whereas a role for PVL could not be detected.

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    • "). This includes the fibronectin-binding protein FnbA, protein A (Spa), alpha toxin, and phenol-soluble modulins (PSMs) (Zielinska et al., 2011; Mrak et al., 2012), all of which have been implicated in various aspects of S. aureus pathogenesis including biofilm formation (Caiazza and O'Toole, 2003; O'Neill et al., 2008; Merino et al., 2009; Otto, 2010; Kobayashi et al., 2011; Lower et al., 2011; Anderson et al., 2012; Edwards et al., 2012; Periasamy et al., 2012; Cassat et al., 2013; Claro et al., 2013). A number of reports have also confirmed that proteases, including some derived from sources other than S. aureus, limit biofilm formation and promote dispersal from an established biofilm (Boles and Horswill, 2008; Park et al., 2012; Chen et al., 2013; Mootz et al., 2013; Sugimoto et al., 2013). "
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    ABSTRACT: We investigated the in vivo relevance of the impact of sarA and saeRS on protease production using derivatives of the USA300 strain LAC. The results confirmed that mutation of saeRS or sarA reduces virulence in a bacteremia model to a comparable degree. However, while eliminating protease production restored virulence in the sarA mutant, it had little impact in the saeRS mutant. Additionally, constitutive activation of saeRS (saeRSC) enhanced the virulence of LAC and largely restored virulence in the isogenic sarA mutant. Based on these results, together with our analysis of the representative virulence factors alpha toxin, protein A (Spa), and extracellular nucleases, we propose a model in which the attenuation of saeRS mutants is defined primarily by decreased production of such factors, while constitutive activation of saeRS increases virulence, and reverses the attenuation of sarA mutants, because it results in both increased production and decreased protease-mediated degradation of these same factors. This regulatory balance was also apparent in a murine model of catheter-associated infection, with the results suggesting that the impact of saeRS on nuclease production plays an important role during the early stages of these infections that is partially offset by increased protease production in sarA mutants.
    Molecular Microbiology 04/2014; 92(6). DOI:10.1111/mmi.12629 · 4.42 Impact Factor
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    • "It forms pores in the cell and mitochondrial membrane of neutrophils and macrophages and thus provokes cell lysis and apoptosis with subsequent liberation of inflammatory mediators [24], [25], [26], [27], [28]. While PVL facilitated experimental CA-MRSA lung and bone infection [29], [30], PVL did not have a significant impact on CA-MRSA virulence in several skin infection models [7], [31]. In addition, cases of PVL-negative CA-MRSA infections have been reported with increasing frequency [7]. "
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    ABSTRACT: We report a case of necrotizing pneumonia in a young patient caused by community acquired-methicillin resistant Staphylococcus aureus (CA-MRSA) in a teaching hospital in the People's Republic of China. The patient had a typical clinical presentation and was successfully treated with antibiotics and intravenous immunoglobulin. A CA-MRSA strain, named SA268, was isolated from the blood of the patient. The isolate was susceptible to most antimicrobial agents, except cephalosporins, penicillins, and β-lactamase inhibitor combinations. Multi-locus sequence typing (MLST) assigned SA268 to ST59, a clone widely spread in eastern Asia. The strain was positive for Panton Valentine Leukocidin (PVL)-encoding genes and SCCmec type V. We sequenced the complete genome of the SA268 isolate. The genome of SA268 was almost identical to that of the Taiwanese ST59 CA-MRSA strains M013 and SA957. However, we observed several differences in gene composition, which included differences in the SCCmec element and several lipoprotein genes that were present in the Taiwanese strains but absent from SA268.
    PLoS ONE 02/2014; 9(2):e89235. DOI:10.1371/journal.pone.0089235 · 3.23 Impact Factor
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    • "In the rabbit pneumonia model, PVL has been demonstrated to have a clear role in mediating severe lung necrosis and inflammation [3]. In contrast, in skin infection, even in the rabbit model, its role remains less clear [4,5]. "
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    ABSTRACT: The community-associated methicillin-resistant S. aureus (CA-MRSA) ST93 clone is becoming dominant in Australia and is clinically highly virulent. In addition, sepsis and skin infection models demonstrate that ST93 CA-MRSA is the most virulent global clone of S. aureus tested to date. While the determinants of virulence have been studied in other clones of CA-MRSA, the basis for hypervirulence in ST93 CA-MRSA has not been defined. Here, using a geographically and temporally dispersed collection of ST93 isolates we demonstrate that the ST93 population hyperexpresses key CA-MRSA exotoxins, in particular alpha-hemolysin, in comparison to other global clones. Gene deletion and complementation studies, and virulence comparisons in a murine skin infection model, showed unequivocally that increased expression of alpha-hemolysin is the key staphylococcal virulence determinant for this clone. Genome sequencing and comparative genomics of strains with divergent exotoxin profiles demonstrated that, like other S. aureus clones, the quorum sensing agr system is the master regulator of toxin expression and virulence in ST93 CA-MRSA. However, we also identified a previously uncharacterized AraC/XylS family regulator (AryK) that potentiates toxin expression and virulence in S. aureus. These data demonstrate that hyperexpression of alpha-hemolysin mediates enhanced virulence in ST93 CA-MRSA, and additional control of exotoxin production, in particular alpha-hemolysin, mediated by regulatory systems other than agr have the potential to fine-tune virulence in CA-MRSA.
    BMC Microbiology 02/2014; 14(1):31. DOI:10.1186/1471-2180-14-31 · 2.73 Impact Factor
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