Innate Immune Response to Norovirus and Biochemical Predictors of Symptoms

Noroviruses (NoV) are the most common cause of acute gastroenteritis in the United States and Europe and are responsible for over 50% of all epidemic gastroenteritis worldwide. However, there is limited understanding of human NoV immunology, in part because of a lack of a cell-culture system. Therefore, we propose a study of the innate immune response to NoV using serum samples from experimental human NoV challenge studies. Preliminary studies suggest that individuals vary in their innate immune response to NoV, however little is known about the clinical implications of those differences. We hypothesize that differences in infection status, symptoms, viral titer, and duration of viral shedding in response to human NoV challenge result from increased pro-inflammatory cytokine production. Improved understanding of the mechanism of host defense will inform development of better prophylaxis (e.g. vaccines), predictive algorithms, and public health prevention strategies. The goal of this study is to elucidate differences in human innate immune response to NoV challenge. To address this goal, we propose: 1. To identify cytokines and chemokines predictive of infection status after NoV challenge and 2. To identify cytokines and chemokines predictive of symptoms, peak viral titer, and duration of viral shedding among infected volunteers. The fellowship applicant aspires to become an academic infectious disease physician, dividing her time between patient care and research. Her long-term goal is to use epidemiologic modeling in order to better understand infectious gastrointestinal disease pathogenesis in order to improve prevention and treatment efforts. Under this fellowship, she will acquire a rigorous methodological foundation in immunology and epidemiology through a combined MD and PhD in epidemiology. This training will be essential to address the proposed research question, develop skills necessary as an independent investigator, and achieve her long-term career goals. Specific goals for this fellowship include: 1. Developing expertise in epidemiologic modeling and techniques in human immunology, 2. Fostering high proficiency in experimental design, 3. Establishing a strong foundation in clinical medicine, 4. Gaining exposure to a variety of clinical disciplines and ongoing population studies, 5. Maintaining an active understanding of trends and developments in human immunology, epidemiology, and clinical medicine, 6. Building excellence in scientific writing and oral presentations, and 7. Actively pursuing career development opportunities. At the start of the funding period, the applicant will have already completed two years of medical studies at Emory University School of Medicine and one year of study in the Epidemiology doctoral program. The proposed research seeks to understand the immunologic basis of NoV infection in humans and to identify clinically-relevant biochemical predictors of infection status, symptoms, viral titer, and duration
of viral shedding. Understanding the innate immune response is critical for advancing the development of NoV therapeutics, creating surveillance tools, and predicting clinical outcomes.