In this mentored clinical scientist training proposal, the applicant will test the hypothesis that expression of global regulatory elements and virulence factors differs among various pulsotypes of methicillin-resistant Staphylococcus aureus (MRSA) and that increased expression of key genes will correlate with virulence in an established rat model of necrotizing pneumonia. In addition, gene expression will be evaluated using an in vivo assay and compared to expression seen in vitro. S. aureus isolates causing community-associated (CA-MRSA) disease will be compared with isolates causing health-care-associated (HA-MRSA) disease. These studies will provide an excellent opportunity for training in molecular biology, bacteriology, and utilization of animal models of disease. The applicant, Christopher P. Montgomery, MD, is an Instructor in the Section of Pediatric Critical Care at the University of Chicago. He formally entered the laboratory of Robert S. Daum, MD, in February 2006, with effort interdigitated with ongoing clinical responsibilities. Dr. Montgomery is in the process of acquiring additional basic science training and has developed a rat model of CA-MRSA necrotizing pneumonia and severe sepsis. The proposed training plan provides 80% protected time, exceptional opportunities to acquire new skills and experience in cellular and molecular biology, as well as didactic training in laboratory techniques and ethical research conduct. The plan also provides interactions with a number of experienced investigators across disciplines, facilitating Dr. Montgomery's transition into successful independent investigation and competitiveness for independent R01 support. CA-MRSA is an important human pathogen causing a variety of severe clinical syndromes, including necrotizing pneumonia and severe sepsis in previously healthy children. Emphasis will be placed on evaluating the differences between the S. aureus genetic background USA300, the dominant circulating CA- MRSA strain in the U.S., and USA400, which it replaced. Insight into the virulence mechanisms of USA300 will shed light on its success in the community.
