The COBRE Program Director (PD), Dr. Dennis Stevens, and the Idaho Veterans Research and Education Foundation (IVREF) seek to establish a well-equipped, multi-disciplinary, broadly-supported and ultimately self- sustaining Collaborative Biomedical Research Center of Excellence (COE) in Emerging/Reemerging Infectious Diseases at its partner institution – the Boise Idaho Veterans Affairs Medical Center (VAMC). Dr. Stevens is a world-recognized leader in the molecular mechanisms of pathogenesis of life-threatening infections. He is also an outstanding clinician, teacher and mentor. His long-term thematic objective for this Center of Excellence is to discover, develop and advance novel new approaches to prevention, diagnosis and treatment of severe life- threatening infections affecting people of all ages worldwide. In keeping with this objective, the specific projects outlined in this COBRE proposal will each investigate the pathogenic mechanisms responsible for a different severe infection, each caused by an emerging/reemerging Gram positive toxin-producing pathogen. Each junior investigator has been carefully selected for his/her unique expertise in a different scientific discipline but havin a shared interest in infectious disease pathogenesis. The PD has recruited exceptionally strong Mentors for each PI, and has developed a comprehensive mentoring plan to ensure successful transition of these junior investigators to independent, federally-funded research careers. He presents a multi- faceted plan to grow and sustain this unique Collaborative Infectious Diseases Center of Excellence in Idaho, including increasing the critical number of investigators and their scientific diversity. The Specific Aims of COBRE Phase I are 1) to support existing junior Infectious Diseases researchers and transition them to research funding independence; 2) to improve existing basic science research infrastructure, including establishment of new core facilities and leveraging of existing NIH IDeA-supported centers; 3) to increase the diversity and critical number of basic science researchers and physician-scientists with interests in Infectious Disease pathogenesis; and 4) expand existing intra- and inter-institutional collaborations to provide exceptional biomedical research and education opportunities in Idaho for gifted undergraduate and graduate/medical students, post-doctoral fellows and physicians. This program builds upon existing strengths and expertise in Infectious Diseases basic science research and academic medicine to foster new discoveries in prevention, diagnosis and treatment of life-threatening infections. An exceptional PD, bright and motivated junior investigators, and the carefully planned elements of this proposal will, in total, work synergistically to ensure a strong, vibrant and sustained Collaborative Biomedical Center of Excellence in Emerging and Reemerging Infectious Diseases that will deliver a continuum of heath care advances and serve as a nexus for such research in Idaho for decades to come.

Staphylococcal, streptococcal and clostridial infections are serious clinical problems worldwide. Infection with these pathogens following trauma, childbirth and/or influenza results in aggressive necrotizing processes that carry a high mortality rate and survivors undergo multiple surgeries, and prolonged intensive care hospitalization and rehabilitation. Emerging resistance of each of these pathogens to conventional antibiotics has reached an all-time high, and hypervirulent strains are spreading worldwide. Thus, the overall objective of this COBRE project is to elucidate, at the cellular and molecular levels, the host/pathogen interactions that contribute to the pathogenesis of these severe, toxin-associated necrotizing infections so that novel targets for diagnosis and treatment can be developed to lessen the incidence, reduce the severity and improve outcomes of these infections.