Staphylococcus aureus is a major health threat in the United States causing skin abscesses, bone infections, joint infections, pneumonias, heart infections, post-operative infections, and infections of implanted devices. Of international concern is the rapidly increasing number of infections caused by methicillin-resistant S. aureus (MRSA). The long-term objective of this proposal is to elucidate S. aureus mechanisms that facilitate evasion of humoral host defense functions as a prerequisite to the development of novel therapies to prevent or attenuate disease. The experimental focus of this proposal is to identify S. aureus cell wall components that bind the host complement regulatory protein factor H and to elucidate the immunomodulatory actions of factor H on the S. aureus surface. Factor H is a serum protein that controls complement activation by destabilizing critical convertases along the complement cascade. The proposed work will build upon our previously published findings that S. aureus binds factor H as well as our new preliminary findings that at least two cell wall components of S. aureus bind purified factor H on overlay Western blot assay. We shall take advantage of the investigator's humoral immune expertise and the proteomic expertise of the George L. Wright Jr. Center for Biomedical Proteomics at EVMS to achieve two specific aims: 1) elucidate the role of factor H binding to S. aureus on complement-mediated host defenses, 2) identify S. aureus cell wall protein(s) that bind factor H.
In aim 1 we will use standard microbiologic and complement techniques to measure the effect of factor H in the destabilization of the alternative pathway C3-convertase and the terminal complement cascade C5-convertases on the S. aureus surface.
In aim 2 we will use standard protein purification techniques coupled with tandem mass spectrometry to identify S. aurues cell wall components that bind factor H.
The proposed project will characterize interactions between Staphylococcus aureus cell wall and the host immuno-regulatory protein factor H. Understanding how this bacteria manipulates factor H will help identify new targets for prevention and treatment of Staphylococcus aureus infections.
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