Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Microbiology and Immunology

Supervisor

Dr. John K. McCormick

Abstract

Superantigens (SAgs) are potent toxins produced by bacteria such as Staphylococcus aureus that function to overactivate T cells resulting in massive cytokine production and immune activation. Despite decades of research on the structure and function of these proteins, as well as their role in severe diseases such as toxic shock syndrome, the question as to why strains of S. aureus produce SAgs and the role that they play in the life cycle of these bacteria remains unanswered. The contribution of SAgs towards pathogenicity and bacterial survival in vivo were assessed using isogenic SAg deletion knockouts in conjunction with SAg-sensitive humanized transgenic HLA-DR4 mice. Since S. aureus are able to successfully colonize human nares in addition to causing infections, the bacterial strains were assessed in a model of nasal colonization as well as a model of bacteremia. Compared to wild-type S. aureus COL and Newman, the SAg-deletion mutants COL Δseb and Newman Δsea were able to establish higher bacterial loads in the nose, suggesting that SAgs are involved in regulating bacterial densities during colonization. Thus, SAgs may act as ‘checkpoints’ of dissemination from the nose. In contrast, Newman Δsea had reduced counts during bacteremia compared to the wild-type strain in a liver-specific phenotype. Staphylococcal enterotoxin A (SEA)-expressing S. aureus Newman induced IFN-γ, IL-12 and chemokine responses which resulted in increased trafficking of CD11b+Ly6G+ neutrophils into the liver. Additionally, wild-type infection resulted in higher numbers of hepatic abscesses containing viable bacteria compared to Newman Δsea representing a specialized in vivo niche for S. aureus. Thus, the mechanism of pathogenicity was due to increased neutrophil infiltration and abscess formation in the liver, as a result of SEA-mediated cytokine and chemokine release. Although staphylococcal SAgs appear to play opposing roles in the different models, the overall function of these toxins appears to be manipulation of the immune system to maintain a niche environment in order to persist and survive.

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