| Notes: | Advisor: Olaf Schneewind.
Thesis (Ph.D.)--The University of Chicago, Division of the Biological Sciences, and The Pritzker School of Medicine, Department of Microbiology, 2012.
Dissertation Abstracts International, Volume: 73-11(E), Section: B.
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| Summary: | Staphylococcus aureus is causative agent of an epidemic of hospital-acquired and community-acquired infections. With the increasing prevalence of antibiotic resistant strains, the need is growing for preventive strategies against staphylococcal disease. Development of a vaccine against S. aureus has proved a tremendous challenge, with numerous strategies being tested in clinical trial. To date, none have shown efficacy. Likely, the successful vaccine will require numerous protein antigens in order to target the virulence arsenal that S. aureus deploys while causing its multitude of disease manifestations. This thesis describes two candidate antigens, coagulase (Coa) and von Willebrand factor binding protein (vWbp). Coa and vWbp co-opt the host coagulation cascade in order to create micro-thrombi that seed organs and allow S. aureus to form abscesses, a hallmark of staphylococcal disease. Pharmacologic inhibition of Coa and vWbp may be one mechanism to protect high-risk patients from developing disease. Furthermore, in combination, active vaccination with Coa and vWbp confer protection against lethal disease and soft tissue infection in mice. However, like protective antigens of other bacteria, Coa and vWbp are variable among isolates. Here, we investigate the immune response that is generated in response to active vaccination with S. aureus and compare that to the requirements to achieve protective immunity, demonstrating that the protective epitopes are not necessarily the most antigenic. Further, we engineered polypeptides that contain the variability of Coa and vWbp that patients in North America are most likely to encounter and demonstrate that vaccination with the polyvalent antigens protects animals against challenge with strains that represent the epidemic Coa serotypes. By targeting the essential epitopes in these key virulence factors, it may be possible to overcome the challenge of antigenic variation.
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