Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Microbiology and Immunology

Supervisor

McCormick, John K.

Abstract

Streptococcus pyogenes is a human-specific bacterial pathogen that commonly colonizes the upper respiratory tract and skin, causing a wide variety of diseases ranging from pharyngitis to necrotizing fasciitis and toxic shock syndrome. S. pyogenes has a repertoire of secreted virulence factors that promote infection and evasion of the host immune system including the cytolysins streptolysin O (SLO) and streptolysin S (SLS). S. pyogenes does not naturally infect the upper respiratory tract of mice, although mice transgenic for MHC class II human leukocyte antigens (HLA) become highly susceptible. Here, we used HLA-transgenic mice to assess the role of both SLO and SLS during both nasopharyngeal and skin infection. Using S. pyogenes MGAS8232 as a model strain, we found that an SLS-deficient strain exhibited a 100-fold reduction in bacterial recovery from the nasopharynx and a 10-fold reduction in bacterial burden in the skin, whereas an SLO-deficient strain did not exhibit any infection defects in these models. Furthermore, depletion of neutrophils significantly restored the bacterial burden of the SLS-deficient bacteria in skin, but not in the nasopharynx. In mice nasally infected with wildtype S. pyogenes, there was a marked change in the localization of the tight junction protein ZO-1 at the site of infection, demonstrating damage to the nasal epithelium that was absent in mice infected with the SLS-deficient strain. Overall, we conclude that SLS is required for the establishment of nasopharyngeal and skin infection in HLA-transgenic mice by S. pyogenes MGAS8232, and we provide evidence that SLS contributes to nasopharyngeal infection through the localized destruction of nasal epithelium. Given the importance of SLS during S. pyogenes infections, we also set out to develop a vaccine targeting the SLS toxin. However, optimization of protein production and purification is still required. This work identifies SLS as a key virulence determinant and has the potential to guide the development of therapies to prevent and treat S. pyogenes infections by targeting SLS-induced pathogenesis.

Summary for Lay Audience

Streptococcus pyogenes is a human-specific bacterial pathogen that causes a massive global burden of disease. Although S. pyogenes acts primarily as a non-symptomatic colonizer of the upper respiratory tract and skin, it may cause mild infections such as strep throat, or more serious diseases such as flesh-eating disease and toxic shock syndrome. S. pyogenes has two toxins, streptolysin O (SLO) and streptolysin S (SLS), which contribute to disease progression by causing cell death. The streptolysins have been extensively studied in mouse models of skin and invasive infections; however, their role in nasal infection is understudied. We found that removal of the SLS toxin from the bacteria caused a significant reduction in the number of bacteria that infected the nasal and skin tissues in mice. Interestingly, the SLO toxin was not a major contributor to disease in either of these infection models. We provided evidence suggesting that SLS targets the mucosal barrier in the nasal tissues of mice to help cause nasal infection. We also show that SLS helps cause skin infection by protecting the bacteria from neutrophils, which are an abundant immune cell found in the body. Since SLS is important for both nasal and skin infection, it has the potential to be a target for vaccine development. Therefore, we also set out to develop a vaccine targeting the SLS toxin. However, optimization of protein production and purification of the vaccine candidate is still required. Overall, strep throat and skin infection are the main S. pyogenes infections, and this work has the potential to guide the development of therapies to prevent and treat S. pyogenes infections by targeting SLS.

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Available for download on Thursday, January 01, 2026

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