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Staphylococcus Aureus alpha-toxin Damages the Tissue Microenvironment during Skin and Soft Tissue Infection
Başlık:
Staphylococcus Aureus alpha-toxin Damages the Tissue Microenvironment during Skin and Soft Tissue Infection
Yazar:
Sampedro, Georgia Rafaella, author. (orcid)0000-0002-3755-6171
ISBN:
9780438088344
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (140 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Advisors: Juliane Bubeck Wardenburg Committee members: Erin Adams; Juliane Bubeck Wardenburg; Sean Crosson; Dominique Missiakas; Lucia B. Rothman-Denes.
Özet:
Staphylococcus aureus is a pathobiont that can cause a range of mild to life-threatening infection in otherwise healthy individuals. While S. aureus disease has a broad tissue tropism, the most common site for both colonization and infection is in the skin. Nearly half of individuals with a S. aureus skin and soft tissue infection (SSTI) suffer from recurrence (Kaplan et al., 2014; Williams et al., 2011; Doung et al., 2010; Chen et al., 2009; Miller et al., 2007, Fritz et al., 2012; Bocchini et al., 2013; Miller et al., 2015). Recurrent infection is a characteristic quality of S. aureus SSTIs, however the precise molecular determinants of susceptibility to recurrence have only recently been investigated. Epidemiologic studies focusing on the immunological correlates of natural human immunity against S. aureus infection have provided initial insight into the key bacterial factors that thwart the host's production of a protective immune response. Elevated antibody titers against an array of staphylococcal cytotoxins minimize the severity of invasive infection and the recurrence of cutaneous S. aureus disease (Adhikari et al., 2012; Fritz et al., 2013). Specifically, serum antibody against one S. aureus cytotoxin, alpha-hemolysin (alpha-toxin, Hla) correlates with protection against recurrent S. aureus skin and soft tissue infection (SSTI) in children (Fritz et al., 2013).
To investigate whether there is a mechanistic link between alpha-toxin expression and the severity of S. aureus reinfection patterns, we developed a mouse model of recurrent S. aureus SSTI mouse model. Using an isogenic Hla mutant in this model we observed that Hla expression during primary infection interferes with development of host immunity against recurrent S. aureus SSTI. Early neutralization of ?-toxin activity either by a dominant-negative toxin mutant or with a small molecule inhibitor against the toxin's cell host receptor, A Disintegrin and Metalloprotease 10, ADAM10, during primary S. aureus SSTI reduces initial and recurrent SSTI abscess severity. Notwithstanding, the mechanism of toxin-mediated cutaneous protection has been perplexing, as toxin injury to keratinocytes and neutrophils have pleiotropic outcomes during S. aureus SSTI. Additionally, while the response that mediates durable immunity against S. aureus skin infections likely involves neutrophil recruitment by an induced T cell-mediated cytokine, IL-17, the contribution of direct toxin-injury on T cells during S. aureus SSTI has remained enigmatic. To evaluate toxin-mediated injury to T cells in cutaneous pathology and pinpoint whether Hla directly impairs the IL-17 induced recruitment of neutrophils by injuring T cells, we excised ADAM10 from peripheral T cells, using Cre-lox technology.
Probing into mechanism, we identified Hla-mediated injury to cutaneous resident innate-like T cells as the cellular gatekeeper of S. aureus SSTI infection outcomes. alpha-Toxin kills both neighboring and distant epidermal T cells adjacent to the site of S. aureus infection. The total decrease in T cells is commensurate with a dampening of IL-17 production, neutrophil activity, abscess formation, and loss of epidermal integrity that results in large wounds. Identification of gamma delta T cells as the innate T cell subset impaired by toxin during early S. aureus SSTI prompted our investigation into whether injury of gamma delta T cells would damage epithelial-immune crosstalk. S. aureus-infected gamma delta T cell reporter mice challenged with toxin-deficient S. aureus revealed critical spatial clustering of the gamma delta T cell highly skewed near the abscess border that is diminished in wild-type S. aureus-infected animals. (Abstract shortened by ProQuest.).
Notlar:
School code: 0330
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(693016.1) | 693016-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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