Thesis (M.S.)--Youngstown State University, 2008. / Includes bibliographical references (leaves 60-63). Also available via the World Wide Web in PDF format.

published_or_final_version / Public Health / Master / Master of Public Health

published_or_final_version / Public Health / Master / Master of Public Health

No description available.

Thesis (M. D.)--University of New South Wales, 2003. / Also available online.

Thesis (M.S.)--Youngstown State University, 2008. / Includes bibliographical references (leaves 75-78). Also available via the World Wide Web in PDF format.

Thesis (M.S.)--Youngstown State University, 2008. / Includes bibliographical references (leaves 32-39). Also available via the World Wide Web in PDF format.

Thesis (Ph. D., Microbiology, Molecular Biology, and Biochemistry)--University of Idaho, July 2007. / Major professor: Gregory A. Bohach. Includes bibliographical references. Also available online (PDF file) by subscription or by purchasing the individual file.

Staphylococcus aureus, particularly the epidemic methicillin-resistant S. aureus (MRSA) USA300 strain, is a major cause of severe necrotizing lung, skin and systemic infection. Although these infections are generally attributed to the pathogen’s multiple toxins, exactly how S. aureus cause disease is not clearly defined. In this research, we sought to establish the role of necroptosis, a programmed form of necrosis, in the pathophysiology of S. aureus pneumonia, skin infection and sepsis. S. aureus, mainly through its multiple toxins, induced RIPK1/RIPK3/MLKL-mediated necroptosis in multiple host cells including human cell lines, freshly obtained alveolar macrophages, peripheral blood macrophages and epithelial cells. S. aureus toxin-associated pore-formation was essential for necroptosis, as cell death was blocked by exogenous K+ or dextran as well as by MLKL inhibition. To understand the role of necroptosis in S. aureus pneumonia, we used Ripk3-/- mice and mice treated with necrostatin-1s (Nec-1s), a potent inhibitor of RIPK1. Inhibition of necroptosis in a mouse model of pneumonia led to significantly improved outcome from S. aureus infection marked by increased bacterial clearance, preserved lung architecture, decreased inflammatory markers in the airway and retention of an anti-inflammatory macrophage population. In contrast, inhibiting necroptosis in vivo during skin infection led to worse outcome as determined by bacterial clearance and lesion sizes, which occurred in spite of the presence of neutrophils, macrophages and γδ T cells. Nec-1s-treated mice and Mlkl-/- mice had significantly larger lesions, increased cytokine response and more S. aureus recovered from the infected areas compared to control groups. We observed a similar outcome in Casp1/4-/- mice, which have limited ability to process IL-1β. Unlike Mlkl-/- mice, Ripk3-/- mice had improved outcome with increased bacterial clearance and decreased inflammation because of the effects of RIPK3 in activating the NLRP3 inflammasome and apoptosis during S. aureus skin infection. Casp1/4-/- immune cells showed a significant defect in their ability to kill S. aureus, whereas Mlkl-/- peritoneal exudate cells and bone marrow-derived macrophages did not. These results show that caspase-1 is essential for bacterial killing whereas necroptosis is necessary for regulating excessive inflammation. Similar to our findings in skin infection, inhibition of the executioner of necroptosis (using Mlkl-/- mice) or pyroptosis (using Casp1/4-/- mice) decreased survival in a mouse model of S. aureus sepsis. Ripk3-/- and wild type mice were equally resistant to S. aureus sepsis. Overall, these findings provide new insights into the complex roles of necrosome components in different tissues during S. aureus infection and may provide potential therapeutic targets to combat these infections.

No description available.