Local Inflammation Exacerbates the Severity of Staphylococcus aureus Skin Infection

Montgomery, Christopher P.; Daniels, Melvin D.; Zhao, Fan; Spellberg, Brad; Chong, Anita S.; Daum, Robert S.

doi:10.1371/journal.pone.0069508

Cited by 31 publications

(27 citation statements)

References 23 publications

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“…There was no apparent effect on bacterial CFU at 24 h postinfection in any of the treatment groups relative to the R347 isotype control. Similar to other reports, lesion size in this model is not dependent on bacterial burden (Table 2) but is primarily AT mediated (9,(21)(22)(23)(24). However, treatment with vancomycin or MEDI4893*-vancomycin accelerated bacterial burden reduction, resulting in significant CFU reductions at 3 (P Ͻ 0.05) and 7 (P Ͻ 0.05) days postinfection relative to R347.…”

Section: Resultssupporting

confidence: 87%

Anti-Alpha-Toxin Monoclonal Antibody and Antibiotic Combination Therapy Improves Disease Outcome and Accelerates Healing in a Staphylococcus aureus Dermonecrosis Model

Hilliard¹,

Datta²,

Tkaczyk³

et al. 2015

Antimicrob Agents Chemother

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c Alpha-toxin (AT) is a major virulence determinant in Staphylococcus aureus skin and soft tissue infection models. We previously demonstrated that prophylactic administration of 2A3, an AT-neutralizing monoclonal antibody (MAb), prevents S. aureus disease in a mouse dermonecrosis model by neutralizing AT-mediated tissue necrosis and immune evasion. In the present study, MEDI4893*, an affinity-optimized version of 2A3, was characterized for therapeutic activity in the dermonecrosis model as a single agent and in combination with two frontline antibiotics, vancomycin and linezolid. MEDI4893* postinfection therapy was found to exhibit a therapeutic treatment window similar to that for linezolid but longer than that for vancomycin. Additionally, when combined with either vancomycin or linezolid, MEDI4893* resulted in reduced tissue damage, increased neutrophil and macrophage infiltration and abscess formation, and accelerated healing relative to those with the antibiotic monotherapies. These data suggest that AT neutralization with a potent MAb holds promise for both prophylaxis and adjunctive therapy with antibiotics and may be a valuable addition to currently available options for the treatment of S. aureus skin and soft tissue infections.

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Section: Resultssupporting

confidence: 87%

Anti-Alpha-Toxin Monoclonal Antibody and Antibiotic Combination Therapy Improves Disease Outcome and Accelerates Healing in a Staphylococcus aureus Dermonecrosis Model

Hilliard¹,

Datta²,

Tkaczyk³

et al. 2015

Antimicrob Agents Chemother

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show abstract

“…Multiple studies in addition to our findings have now illustrated a lack of direct, temporal correlation between S. aureus recovery from the infected tissue and measurements of disease severity [8,9,22,45,50], suggesting that the clinical manifestations of disease represent the aggregate balance of bacterial insults to resident and recruited cells and the host inflammatory response [51]. This response can be well-directed to facilitate pathogen clearance in the given tissue, or overly aggressive, leading to exacerbated injury.…”

Section: Discussionmentioning

confidence: 69%

“…Together, these data suggest that toxin-induced immunostimulation establishes a pro-inflammatory skin environment that benefits the host, limiting the consequences of S. aureus infection. In contrast to these findings, a recent study examining athymic nude mice noted decreased staphylococcal skin lesion size in these mice [45]. The authors concluded that local inflammation promotes increased severity of S. aureus skin infection, a finding that will require further mechanistic investigation in light of the more substantial alterations of immunologic function in nude mice.…”

Section: Discussionmentioning

confidence: 92%

Tissue-Specific Patterning of Host Innate Immune Responses by <b><i>Staphylococcus aureus</i></b> α-Toxin

Becker¹,

Berube²,

Sampedro³

et al. 2014

J Innate Immun

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Immunomodulatory cytotoxins are prominent virulence factors produced by Staphylococcus aureus, a leading cause of bacterial sepsis, skin infection, and pneumonia. S. aureus α-toxin is a pore-forming toxin that utilizes a widely expressed receptor, ADAM10, to injure the host epithelium, endothelium, and immune cells. As each host tissue is characterized by a unique composition of resident cells and recruited immune cells, the outcome of α-toxin-mediated injury may depend on the infected tissue environment. Utilizing myeloid lineage-specific Adam10 knockout mice, we show that α-toxin exerts tissue-specific effects on innate immunity to staphylococcal infection. Loss of ADAM10 expression exacerbates skin infection, yet affords protection against lethal pneumonia. These diverse outcomes are not related to altered immune cell recruitment, but rather correlate with a defect in toxin-induced IL-1β production. Extension of these studies through analysis of ADAM10 double-knockout mice affecting both the myeloid lineage and either the skin or lung epithelium highlight the prominence of toxin-induced injury to the epithelium in governing the outcome of infection. Together, these studies provide evidence of tissue specificity of pore-forming cytotoxin action in the modulation of host immunity, and illustrate that the outcome of infection is a collective manifestation of all effects of the toxin within the tissue microenvironment.

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“…Additionally, bacterial biofilms appear to play an important role in increasing the difficulty of treating these ulcers (40). Furthermore, it has been proven recently that the clinical severity of S. aureus skin infection is driven by the inflammatory response to the bacteria rather than the bacterial burden (42)(43)(44). Taken together, the characteristics of the presented peptides with combined bactericidal, antibiofilm, and anti-inflammatory effect may offer an effective way for treating staphylococcal skin infection.…”

Section: Discussionmentioning

confidence: 99%

Targeting Methicillin-Resistant Staphylococcus aureus with Short Salt-Resistant Synthetic Peptides

Mohamed

Hamed

Panitch

et al. 2014

Antimicrob Agents Chemother

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bThe seriousness of microbial resistance combined with the lack of new antimicrobials has increased interest in the development of antimicrobial peptides (AMPs) as novel therapeutics. In this study, we evaluated the antimicrobial activities of two short synthetic peptides, namely, RRIKA and RR. These peptides exhibited potent antimicrobial activity against Staphylococcus aureus, and their antimicrobial effects were significantly enhanced by addition of three amino acids in the C terminus, which consequently increased the amphipathicity, hydrophobicity, and net charge. Moreover, RRIKA and RR demonstrated a significant and rapid bactericidal effect against clinical and drug-resistant Staphylococcus isolates, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA), linezolid-resistant S. aureus, and methicillin-resistant Staphylococcus epidermidis. In contrast to many natural AMPs, RRIKA and RR retained their activity in the presence of physiological concentrations of NaCl and MgCl 2 . Both RRIKA and RR enhanced the killing of lysostaphin more than 1,000-fold and eradicated MRSA and VRSA isolates within 20 min. Furthermore, the peptides presented were superior in reducing adherent biofilms of S. aureus and S. epidermidis compared to results with conventional antibiotics. Our findings indicate that the staphylocidal effects of our peptides were through permeabilization of the bacterial membrane, leading to leakage of cytoplasmic contents and cell death. Furthermore, peptides were not toxic to HeLa cells at 4-to 8-fold their antimicrobial concentrations. The potent and salt-insensitive antimicrobial activities of these peptides present an attractive therapeutic candidate for treatment of multidrug-resistant S. aureus infections.

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Local Inflammation Exacerbates the Severity of Staphylococcus aureus Skin Infection

Cited by 31 publications

References 23 publications

Anti-Alpha-Toxin Monoclonal Antibody and Antibiotic Combination Therapy Improves Disease Outcome and Accelerates Healing in a Staphylococcus aureus Dermonecrosis Model

Anti-Alpha-Toxin Monoclonal Antibody and Antibiotic Combination Therapy Improves Disease Outcome and Accelerates Healing in a Staphylococcus aureus Dermonecrosis Model

Tissue-Specific Patterning of Host Innate Immune Responses by <b><i>Staphylococcus aureus</i></b> α-Toxin

Targeting Methicillin-Resistant Staphylococcus aureus with Short Salt-Resistant Synthetic Peptides

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