Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

Abstract

Staphylococcus aureus is known to cause severe systemic infection with high mortality rates. Antibiotics are the only approved therapy for patients, but the widespread prevalence of antibiotic resistant strains limits treatment efficacy, and many patients succumb to the disease. Many probiotic agents are commercially available, but the mechanisms by which they benefit are not known. Understanding these mechanisms will help develop novel therapeutics that can improve healthcare, including systemic infections by S. aureus. Bacillus subtilis is a probiotic bacterium that produces an exopolysaccharide (EPS) that induces anti inflammatory macrophages (MΦ). We tested if EPS could be used for systemic S. aureus infections in mice and found that EPS treated mice had improved outcomes, reducing bacterial load and inflammation. We tested for the mechanism behind this protection and found that EPS induced MΦ, while they resemble anti inflammatory M2 MΦ, restrict the growth of internalized S. aureus through reactive oxygen species like that of pro inflammatory M1 MΦ. In addition, EPS-induced MΦ retained their anti inflammatory capacity to limit T cell activation in response to S. aureus superantigens, suggesting that EPS induces a "hybrid" MΦ population with both M1 and M2 like qualities, limiting S. aureus growth. In vivo, we found that S. aureus induces interferon gamma (IFN-γ) production through natural killer (NK) cells, a way to manipulate the host immune system for its own pathogenesis. Furthermore, EPS-treated mice did not make IFN-γ in response to S. aureus, suggesting that EPS protects hosts from S. aureus also by limiting IFN-γ production. We suggest that EPS primes the host immune system to bolster its antimicrobial activity and also limit inflammation, which prevents S. aureus from manipulating the host response for its own pathogenesis, leading to reduced disease burden and improving outcomes. By our understanding of EPS mechanism for protection, we have identified a potential strategy to help patients with systemic S. aureus infection.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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