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Staphylococcus aureus Skin Infections: Understanding the Roles of Host and Pathogen
Ridder, Miranda
Ridder, Miranda
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Abstract
Staphylococcus aureus is a leading cause of skin and soft tissue infections (SSTIs). There has been intense investigation into what bacterial factors contribute to skin pathogenesis, but it remains unclear which host factors are important and when they are important. While studies to date have provided snapshots of the immune response to S. aureus SSTIs, the full kinetic immune response to S. aureus subcutaneous skin infection has not been characterized. In this dissertation, I will demonstrate the importance of both bacteria and host factors by providing evidence that FakA and YjbIH contribute to pathogenesis and then by characterizing the kinetic immune response to a wild-type subcutaneous infection. Without FakA, skin disease is more severe: skin lesions are larger and there is increased production of pro-inflammatory cytokines. Deletion of yjbIH causes less severe skin disease: a necrotic lesion does not form and there is a reduction in bacterial titers and production of pro-inflammatory cytokines. To define the kinetic immune response, we used female C57BL/6J mice and USA300 S. aureus to examine the host-pathogen interface from 8h to 15 days post-infection (d.p.i.) with the following outcomes measured: lesion size, bacterial titers, local cytokine and chemokine levels, phenotype of responding leukocytes, and histopathology and Gram staining of skin tissue. Lesions were largest at 1 d.p.i. with peak necrotic tissue area at 3 d.p.i. and were largely resolved by 15 d.p.i. During early infection, bacterial titers were high, neutrophils were the most abundant immune cell, there was a decrease in most leukocyte populations relative to those found in uninfected skin, and many different cytokines were produced. Histopathologic analysis demonstrated swift and extensive keratinocyte death and robust and persistent neutrophil infiltration. Gram staining revealed subdermal S. aureus colonization and, later, limited migration into upper skin layers. IL-17A/F were only detected starting 5 d.p.i. and coincided with an immediate decrease in bacterial numbers in the following days. After 9 days, neutrophils were no longer the most abundant immune cell present as most other leukocyte subsets returned to pre-infection levels, and surface wounds resolved coincident with declining bacterial titers. Collectively, these data illustrate a dynamic immune response to S. aureus skin infection and suggest a key role for precisely timed IL-17 production for infection clearance and healthy tissue formation. Overall, the work in this dissertation supports the idea that both the bacteria and the host contribute to skin pathogenesis by showing that FakA and YjbIH contribute to disease and that the host response is dynamic over time.
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2022-01-01
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University of Kansas
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Keywords
Microbiology, Immunology, MRSA, Staphylococcus aureus