Graduation Date

Summer 8-18-2017

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Pathology & Microbiology

First Advisor

Dr. Tammy Kielian

Second Advisor

Dr. Jessica Snowden

Third Advisor

Dr. Paul Fey

Abstract

Staphylococcus aureus (S. aureus) is a leading cause of community- and healthcare-associated infections and has a propensity to form biofilms. Biofilm infections are recalcitrant to host immune-mediated clearance as well as antibiotics, making them exceptionally difficult to eradicate. The biofilm environment has been shown to skew the host immune response towards an anti-inflammatory phenotype, characterized by alternatively activated macrophages, recruitment of myeloid-derived suppressor cells (MDSCs), and minimal neutrophil and T cell infiltrates. Our laboratory has attempted to redirect the host immune response towards one that would favor bacterial clearance by employing strategies to augment pro-inflammatory mechanisms. One such approach was to utilize lipopolysaccharide (LPS), which was expected to promote pro-inflammatory activation of peripheral immune cells infiltrating the biofilm and subsequent clearance of infection. This theory was partially correct, as pro-inflammatory cytokines in the serum were significantly increased, and peripheral immune cells in the blood were more effective at killing S. aureus ex vivo following LPS treatment; however biofilm infection was exacerbated. Specifically, bacterial titers increased nearly 2-log with administration of LPS, and although infiltration of Ly6G+Ly6C+ MDSCs was decreased, a new population of Ly6GintLy6C+ cells appeared. Additionally, both Ly6G+Ly6C+ and Ly6GintLy6C+ populations were more suppressive with LPS treatment, partially explaining the expansion of S. aureus biofilm burdens. This study highlights the resilient nature of S. aureus biofilm infections to influence the immune response, particularly through MDSCs, even in the face of a strong pro-inflammatory stimulus. Gaining a better understanding of the mechanisms that cause this ineffective host immune response to staphylococcal biofilms is a necessary step towards eradicating these debilitating infections.

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