Abscess Formation and Alpha-Hemolysin Induced Toxicity in a Mouse Model of Staphylococcus aureus Peritoneal Infection

Rauch, Sabine; DeDent, Andrea C.; Kim, Hwan Keun; Wardenburg, Juliane Bubeck; Missiakas, Dominique; Schneewind, Olaf

doi:10.1128/iai.00442-12

Cited by 81 publications

(82 citation statements)

References 51 publications

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“…Indeed, it has been demonstrated to be essential for disease in several animal models of infection (5)(6)(7)(8)(9)(10)(11). Considering its importance, it is not surprising that this toxin is under tight regulatory control to ensure that its production is adapted to the varied microenvironments and immune modulators present within the host.…”

Section: Discussionmentioning

confidence: 99%

“…VfrB impacts virulence in an SSTI model. Alpha-hemolysin has been shown previously to be important in a variety of infection models (5)(6)(7)(8)(9)(10)(11)(12), and proteases are thought to contribute to pathogenesis by modulating secreted virulence factors and degrading host proteins (21,(28)(29)(30)(31)(32)(33)(34). To assess the contribution of VfrBregulated virulence factors in vivo, we chose a mouse model of dermonecrosis due to the following considerations: (i) S. aureus is the dominant cause of all skin and soft tissue infections (SSTI) in patients presenting to emergency departments in the United States (49); (ii) more than 90% of all S. aureus infections are SSTI (50, 51); (iii) our wild-type strain is derived from an SSTI isolate (39,52); and (iv) both alpha-hemolysin (8) and proteases have been demonstrated to contribute to skin infections (21).…”

Section: Figmentioning

confidence: 99%

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Identification of the Staphylococcus aureus vfrAB Operon, a Novel Virulence Factor Regulatory Locus

et al. 2014

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b During a screen of the Nebraska Transposon Mutant Library, we identified 71 mutations in the Staphylococcus aureus genome that altered hemolysis on blood agar medium. Although many of these mutations disrupted genes known to affect the production of alpha-hemolysin, two of them were associated with an apparent operon, designated vfrAB, that had not been characterized previously. Interestingly, a ⌬vfrB mutant exhibited only minor effects on the transcription of the hla gene, encoding alphahemolysin, when grown in broth, as well as on RNAIII, a posttranscriptional regulatory RNA important for alpha-hemolysin translation, suggesting that VfrB may function at the posttranscriptional level. Indeed, a ⌬vfrB mutant had increased aur and sspAB protease expression under these conditions. However, disruption of the known secreted proteases in the ⌬vfrB mutant did not restore hemolytic activity in the ⌬vfrB mutant on blood agar. Further analysis revealed that, in contrast to the minor effects of VfrB on hla transcription when strains were cultured in liquid media, the level of hla transcription was decreased 50-fold in the absence of VfrB on solid media. These results demonstrate that while VfrB represses protease expression when strains are grown in broth, hla regulation is highly responsive to factors associated with growth on solid media. Intriguingly, the ⌬vfrB mutant displayed increased pathogenesis in a model of S. aureus dermonecrosis, further highlighting the complexity of VfrB-dependent virulence regulation. The results of this study describe a phenotype associated with a class of highly conserved yet uncharacterized proteins found in Gram-positive bacteria, and they shed new light on the regulation of virulence factors necessary for S. aureus pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

Identification of the Staphylococcus aureus vfrAB Operon, a Novel Virulence Factor Regulatory Locus

et al. 2014

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“…This study utilized MRSA strain Xen 30 (Xenogen/Caliper Life Sciences, Inc.), which was derived from S. aureus strain 16 and contains a luxABCDE operon in the chromosome, allowing for detection via bioluminescence in vivo (30). Although MRSA strains can vary in alphatoxin production (31)(32)(33), the virulence of the study strain was confirmed as equivalent to that of USA300 in the model as used in our prior studies (25). The virulence of strain Xen 30 was assessed in a previous study and demonstrated to be equivalent to that of other clinically relevant MRSA strains in the SSSI murine model (25).…”

Section: Methodsmentioning

confidence: 99%

Nonredundant Roles of Interleukin-17A (IL-17A) and IL-22 in Murine Host Defense against Cutaneous and Hematogenous Infection Due to Methicillin-Resistant Staphylococcus aureus

et al. 2015

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“…Using NRS384 as the template, DNA flanking the codon for histidine 35 of Hla was amplified by PCR. The two resulting PCR products were digested with BsaI and cloned (37) into pRP1276 that had been digested with BamHI and SalI, generating pRP1308, which carries the H35L mutation in the Hla sequence, previously shown to reduce hemolytic activity and virulence (38)(39)(40)(41).…”

Section: Methodsmentioning

confidence: 99%

Epicutaneous Model of Community-Acquired Staphylococcus aureus Skin Infections

et al. 2013

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bStaphylococcus aureus is one of the most common etiological agents of community-acquired skin and soft tissue infection (SSTI). Although the majority of S. aureus community-acquired SSTIs are uncomplicated and self-clearing in nature, some percentage of these cases progress into life-threatening invasive infections. Current animal models of S. aureus SSTI suffer from two drawbacks: these models are a better representation of hospital-acquired SSTI than community-acquired SSTI, and they involve methods that are difficult to replicate. For these reasons, we sought to develop a murine model of community-acquired methicillin-resistant S. aureus SSTI (CA-MRSA SSTI) that can be consistently reproduced with a high degree of precision. We utilized this model to begin to characterize the host immune response to this type of infection. We infected mice via epicutaneous challenge of the skin on the outer ear pinna using Morrow-Brown allergy test needles coated in S. aureus USA300. When mice were challenged in this model, they developed small, purulent, self-clearing lesions with predictable areas of inflammation that mimicked a human infection. CFU in the ear pinna peaked at day 7 before dropping by day 14. The T h 1 and T h 17 cytokines gamma interferon (IFN-␥), interleukin-12 (IL-12) p70, tumor necrosis factor alpha (TNF-␣), IL-17A, IL-6, and IL-21 were all significantly increased in the draining lymph node of infected mice, and there was neutrophil recruitment to the infection site. In vivo neutrophil depletion demonstrated that neutrophils play a protective role in preventing bacterial dissemination and fatal invasive infection.

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Abscess Formation and Alpha-Hemolysin Induced Toxicity in a Mouse Model of Staphylococcus aureus Peritoneal Infection

Abstract: ABSTRACTStaphylococcus aureusis a frequent cause of skin infection and sepsis in humans. Preclinical vaccine studies withS. aureushave used a mouse model with intraperitoneal challenge and survival determination as a… Show more

Cited by 81 publications

References 51 publications

Identification of the Staphylococcus aureus vfrAB Operon, a Novel Virulence Factor Regulatory Locus

Identification of the Staphylococcus aureus vfrAB Operon, a Novel Virulence Factor Regulatory Locus

Nonredundant Roles of Interleukin-17A (IL-17A) and IL-22 in Murine Host Defense against Cutaneous and Hematogenous Infection Due to Methicillin-Resistant Staphylococcus aureus

Epicutaneous Model of Community-Acquired Staphylococcus aureus Skin Infections

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