This proposal details a training plan for the continued development of Dr. Allison Bartlett as an academic pediatric infectious disease physician-scientist. She has completed her clinical training in pediatrics and infectious diseases, and has joined the faculty of the Department of Pediatrics at Baylor College of Medicine. Using the atmosphere of collaboration in the Texas Medical Center, Dr. Bartlett has assembled a team of mentors and advisors to assist in her training with a goal of strengthening her research skills in host- pathogen interactions. The candidate's mentor, Magnus Hook, Ph.D., director of the Center for Extracellular Matrix Biology at the Institute of Biosciences and Technology, is a recognized leader in the study of molecular mechanisms of microbial adhesion to host extracellular matrix molecules. The Center has well- developed techniques for assessing cell adherence and has experience with mouse models of S. aureus pneumonia and sepsis. Her co-mentor, Burton Dickey, M.D. Chair of Pulmonary Medicine at M.D. Anderson Cancer Center, was selected for his expertise in airway inflammation and pathogen defense. Drs. Hook and Dickey collaborate frequently and have extensive experience training postdoctoral fellows. An advisory committee, which met regularly during the candidate's fellowship training, will continue its active role in her research development and career planning. The candidate is also pursuing a Master's Degree in Clinical Investigation through the Clinical Scientist Training Program at Baylor College of Medicine, to supplement her laboratory learning with graduate-level coursework. Dr. Bartlett's research will focus on Staphylococcus aureus attachment to host cells mediated by a family of surface proteins called MSCRAMMs (Microbial Surface Components Recognizing Adhesive Matrix Molecules), an important initial step in colonization and invasive disease. We hypothesize that the MSCRAMM serine-aspartate repeat protein D (SdrD) is a key adhesin mediating attachment to host cells via interaction with a specific receptor, thereby influencing tissue specificity of disease. We further hypothesize that SdrD is a virulence factor in pneumonia and sepsis. We propose to address our hypotheses in the following Specific Aims: (1) Determine: (a) the host cell specificity of SdrD-mediated staphylococcal adherence, (b) the adhesion potential of SdrD in a relevant clinical strain, and the (c) frequency and sequence variation of the sdrD gene in a collection of clinical isolates from pediatric patients;(2) Identify the host cell receptor(s) for SdrD;(3) Determine the role of SdrD in vivo in mouse models of pneumonia and sepsis.
Staphylococcus aureus is a major cause of infections including cellulitis and osteomyelitis, pneumonia, and sepsis. Attachment of bacteria to host cells is an important initial step in development of disease. The above studies will investigate the role of specific adhesin-host interactions which is critical for developing preventative and therapeutic strategies against this significant pathogen and threat to public health.