Innate Immune Response to Norovirus and Biochemical Predictors of Symptoms

描述（由申请方提供）：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，对人类NoV免疫学的理解有限，部分原因是缺乏细胞培养系统。因此，我们提出使用来自实验性人NoV攻击研究的血清样品研究对NoV的先天免疫应答。初步研究表明，个体对NoV的先天免疫反应各不相同，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、病毒滴度和病毒脱落持续时间的差异是由于促炎细胞因子产生增加所致。对宿主防御机制的进一步理解将为更好的预防（例如疫苗），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先天免疫应答对NoV攻击的差异。为了实现这一目标，我们建议：1。鉴定预测NoV攻击后感染状态的细胞因子和趋化因子，以及2.在受感染志愿者中鉴定预测症状、峰值病毒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，将她的时间分配在病人护理和研究之间。她的长期目标是使用流行病学建模，以更好地了解传染性胃肠道疾病的发病机制，以改善预防和治疗工作。根据这项奖学金，她将通过流行病学的MD和博士学位获得免疫学和流行病学的严格方法学基础。这种培训将是必不可少的，以解决拟议的研究问题，发展必要的技能，作为一个独立的调查员，并实现她的长期职业目标。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的专业知识，2。培养高水平的实验设计能力; 3.奠定坚实的临床医学基础，4。接触各种临床学科和正在进行的人群研究，5。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，6。建立卓越的科学写作和口头报告，和7。积极寻求职业发展机会。在资助期开始时，申请人将已经在埃默里大学医学院完成两年的医学研究，并在流行病学博士课程中完成一年的研究。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 病毒脱落了解先天免疫反应对于推进NoV疗法的开发、创建监测工具和预测临床结果至关重要。

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.