Immune profiling to stratify Clostridioides difficile infection outcomes

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Candidate: Dr. Gregory Madden is an Assistant Professor of Infectious Diseases at the University of Virginia with experience in research regarding the diagnosis, epidemiology, and pathogenesis of C. difficile infection. Career Development Plan and Goals: The proposed K23 Mentored Career Development Award will uniquely establish Dr. Madden as a translational researcher with experience in host-pathogen interactions and advanced modeling techniques. Training activities for the award include graduate-level coursework in clinical trial design and statistical modeling, culminating with a Master’s Degree of Science in Clinical Research. Research Plan: Clostridioides difficile is the leading healthcare-associated pathogen in the US. Evidence suggests that the host innate immune system (particularly Type 2, or eosinophil-mediated immunity), fecal C. difficile burden, and Binary toxin play important roles in C. difficile infection. However, no model to predict outcomes of C. difficile infection takes these factors into account. Data from our lab show that eosinopenia, specific biomarkers of pathogenic immunity (i.e., Soluble ST2 Receptor, IL-6), fecal organism burden, and the presence of fecal Binary Toxin are associated with increased C. difficile mortality. Dr. Madden, proposes to: 1) Construct a clinical-immunologic database of C. difficile patients to develop a robust biomarker-based model for outcomes of C. difficile infection and 2) Prospectively validate this model alongside the leading clinical models. Successful completion of the proposed research will create a validated immune profile for C. difficile infection outcomes that reflects our latest understanding of pathogenesis. In addition, we will identify a much-needed optimal approach for researchers and clinicians to stratify life-threatening C. difficile infection at the time of diagnosis. Mentors: Dr. Madden’s mentor is Dr. William A. Petri, MD, PhD, a leading researcher in the field of host defense against C. difficile. Internal advisors and collaborators have diverse expertise in hospital epidemiology (Dr. Costi Sifri, accomplished practicing hospital epidemiologist with a background studying molecular pathogenesis), immunology (Dr. Melanie Rutkowsi, PhD, biostatistics/machine learning (Jennie Ma, PhD), clinical trial design (Dr. James A. Platts-Mills, MD), and molecular diagnostics (Eric R. Houpt, MD). Environment: The University of Virginia is world-renowned for its work in enteric diseases and is one of the first institutions to establish a School dedicated to Data Science. The University of Virginia Data Science Institute, School of Public Health Sciences, Office of Hospital Epidemiology, and the Petri Lab will provide the resources as well as the diverse and stimulating environment for this Candidate to flourish as an independent investigator in this cutting-edge field.