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 opportunistic pathogen that exploits an assortment of surface molecules to overcome host clearing mechanisms and cause a substantial burden of acute and chronic diseases worldwide. In the present work we utilize the M18 serotype S. pyogenes strain MGAS8232 to demonstrate that genomic deletion of thehyaluronic acid capsule significantly reduces bacterial densities in murine models of experimental nasopharyngeal and skin infections. We show that anti-Ly6G administration recovers the deteriorated burden by unencapsulated bacteria at both infection sites, indicating that capsule expression promotes resistance to neutrophil-mediated clearance during acute infections. We also evaluated the efficacy of serotype-specific immunity against the surface M protein and show that induction of serum M protein-specific IgG levels by monovalent M protein immunizations is not sufficient to protect mice from acute nasopharyngeal or skin challenges. Lastly, we implemented a recurring infection model to evaluate whether M protein expression is a possible driver of long-term cardiac complications. Multiple homologous infections with S. pyogenes MGAS8232 altered left ventricle filling dynamics and weakened ejection fractions by echocardiography compared to control inoculations with PBS or infection with S. pyogenes lacking its M protein, suggesting that M protein expression is directly associated with cardiac alterations. Together, this work provides deeper understandings on how S. pyogenes avoids innate clearance to establish superficial infections and reveals physiological insights on the development of cardiac impediments following multiple acute infections. This work has also provided valuable insights that will help guide future vaccine development strategies against this globally prominent pathogen.

Summary for Lay Audience

Streptococcus pyogenes is a human-specific bacterium responsible for an enormous burden of disease worldwide. Pharyngitis, more commonly known as ‘strep throat,’ is reported in over 600 million people each year, and impetigo, a benign skin infection, affects more than 100 million people annually. Since there is currently no licensed vaccine available it is critical to understand the bacterial factors that promote initial stages of infection and induce severe diseases. In this study we examined how the S. pyogenes capsule helps support bacterial infection and found that removal of the capsule dramatically weakened the ability to cause nasal and skin infections in mice. We discovered that the capsule specifically protected bacteria from killing by a key immune cell, the neutrophil. We also evaluated the efficacy of a S. pyogenes vaccine against the surface M protein and found that vaccination against the M protein triggers antibody production but does not provide any protection from nasal or skin infections. Lastly, we performed multiple S. pyogenes nasal infections in mice and examined the impact on heart function using echocardiograms. Interestingly, we demonstrate that multiple S. pyogenes infections results in reduced left ventricle function only when the M protein is expressed by the bacteria. Overall, this work reveals how S. pyogenes overcomes the human immune system to establish infection and demonstrates that the M protein is an ineffective vaccine target that may contribute to heart dysfunction.

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