Innate Immune Response to Norovirus and Biochemical Predictors of Symptoms

描述（由申请人提供）：诺如病毒（NoV）是美国和欧洲急性胃肠炎的最常见原因，占全球所有流行性胃肠炎的50%以上。然而，由于缺乏细胞培养系统，对人类NoV免疫学的了解有限。因此，我们建议使用实验性人类NoV攻击研究的血清样本来研究对NoV的先天免疫反应。初步研究表明，个体对NoV的先天免疫反应不同，但对这些差异的临床意义知之甚少。我们假设感染状态、症状、病毒滴度和病毒释放持续时间的差异是由促炎细胞因子产生增加引起的。对宿主防御机制的进一步了解将为更好的预防（如疫苗）、预测算法和公共卫生预防策略的发展提供信息。本研究的目的是阐明人类对NoV攻击的先天免疫反应的差异。为实现这一目标，我们提出：目的：确定预测感染状态的细胞因子和趋化因子。在受感染的志愿者中，确定预测症状、病毒峰值滴度和病毒脱落持续时间的细胞因子和趋化因子。奖学金申请人渴望成为一名学术传染病医生，将她的时间分配给病人护理和研究。她的长期目标是利用流行病学建模，以便更好地了解感染性胃肠道疾病的发病机制，以提高预防和治疗的努力。在此奖学金下，她将获得免疫学和流行病学的严谨方法论基础，并获得流行病学的医学博士和博士学位。这种培训对于解决提出的研究问题、培养作为独立研究者所必需的技能以及实现她的长期职业目标至关重要。该奖学金的具体目标包括：1。发展流行病学建模和人类免疫学技术方面的专业知识；2 .培养实验设计能力；3 .夯实临床医学基础；4 .接触各种临床学科和正在进行的人口研究；保持对人类免疫学、流行病学和临床医学的趋势和发展的积极理解；建立卓越的科学写作和口头报告；积极寻求职业发展机会。在资助期开始时，申请人必须在埃默里大学医学院完成两年的医学学习和一年的流行病学博士课程学习。拟议的研究旨在了解人类NoV感染的免疫学基础，并确定感染状态、症状、病毒滴度和持续时间的临床相关生化预测因子

DESCRIPTION (provided by applicant): 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.