Date of Degree
PhD (Doctor of Philosophy)
Patrick M. Schlievert
Staphylococcus aureus is the leading cause of infective endocarditis in the United States. Infective endocarditis (IE) is defined as an infection of the endocardium, typically involving the heart valves. The hallmark features of IE are vegetations. Vegetations are cauliflower-like, stratified biofilms of bacteria and host factors that develop on the valve leaflets of the heart. The mechanisms of how vegetations form are not well understood, and as a consequence the bacterial factors that are important for development of IE are not well defined. My studies focus on the role of a family of S. aureus exoproteins known as superantigens and their role in IE.
Superantigens (SAgs) are a class of secreted virulence factors that have been extensively studied for their role in systemic diseases such as toxic shock syndrome (TSS), pneumonia, and food poisoning. The SAg protein family is comprised of 23 distinct members designated as staphylococcal enterotoxin (SE) or enterotoxin-like (SEl) and toxic shock syndrome toxin-1 (TSST-1). The term superantigen is derived from the ability of SAgs to interact with the immune system, resulting in a nearly 3000-fold increase in activation when compared to standard antigens. SAgs have a defined structure that is composed of 2 domains, a carboxy-terminal beta-grasp domain and amino-terminal oligosaccharide/oligonucleotide binding (OB) fold. Defined groups of SAgs are associated with S. aureus strains isolated from specific diseases, but few studies have been done to determine the role of SAgs in diseases outside of TSS and food poisoning.
The enterotoxin gene cluster (egc) is a group of 6 SAgs (selo, selm, sei, selu, seln, and seg) assembled into an operon-like cluster that is present in the majority of S. aureus strains isolated from IE patients. My studies have determined that the egc is able to induce vegetations when expressed in avirulent S. aureus strains. This is the first time the egc has been directly associated with IE. I further characterized the capacity of the individual egc proteins to induce vegetations. Four (selo, selm, sei, and selu) of the 6 egc SAgs were able to induce vegetation formation. This is the first time the individual egc proteins have been characterized and directly associated with IE. I also demonstrated that the egc proteins may not be exclusively expressed as a single polycistronic transcript but that selu and seg contain promoter elements that may drive their individual expression. Lastly, I provide evidence that the egc SAgs may be regulated by MgrA, a global regulator of S. aureus associated with virulence factor expression.
Staphylococcus aureus is the cause of millions of infections per year in the United States. S. aureus is the leading cause of a dangerous and invasive disease known as infective endocarditis (IE). IE is an infection of the heart that leads to cauliflower-like growths known as vegetations that develop on the heart valves. Vegetations are composed of bacteria and host factors. Vegetations act as reservoirs of infection and can fragment leading to debilitating complications such as strokes, kidney failure, heart failure, and lung damage. The invasive nature and devastating complications of IE necessitate the identification of bacterial factors that are important in development of this disease.
S. aureus secretes proteins known as superantigens (SAgs) that have been studied for their role in toxic shock syndrome, food poisoning, and pneumonia. They have the ability to interact with the immune system and directly with tissues. In my studies, I identified the enterotoxin gene cluster (egc) SAgs as critical factors involved in the development of vegetations. The egc encodes 6 SAgs and is present in the majority of S. aureus strains isolated from IE patients. My studies characterized the capacity of each of the proteins in the egc to cause vegetations. I determined that 4 of the 6 egc proteins were individually capable of causing vegetations and displayed differing capacities to cause disease. This is the first time that the egc was directly associated with disease and that the individual egc proteins were characterized for their ability to cause disease.
publicabstract, Enterotoxin Gene Cluster, Infective Endocarditis, Staphylococcus aureus, Superantigens
x, 97 pages
Includes bibliographical references (pages 81-97).
Copyright 2015 Christopher Stach