Innate Immune Response to Norovirus and Biochemical Predictors of Symptoms

对诺如病毒的先天免疫反应和症状的生化预测因子

• 批准号: 8594805
• 负责人: Kira Newman
• 金额: $ 4.72万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-12 至 2018-09-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8594805
• 关键词: Acute; Address; Advanced Development; Algorithms; Animal Model; Antibodies; Biochemical; Bioterrorism; Categories; Cattle; Cell Culture System; Centers for Disease Control and Prevention (U.S.); Classification; Clinical; Clinical Medicine; Communicable Diseases; Data Analyses; Detection; Developed Countries; Development; Diarrhea; Discipline; Doctor of Philosophy; Dose; Economic Burden; Enrollment; Epidemic; Epidemiology; Equation; Europe; Excretory function; Exhibits; Experimental Designs; Exposure to; Family suidae; Feces; Fellowship; Fostering; Foundations; Funding; Gastroenteritis; Gastrointestinal Diseases; Genetic; Goals; Host Defense Mechanism; Hour; Human; Immune; Immune response; Immunity; Immunoglobulins; Immunologics; Immunology; Individual; Infection; Inflammatory; Inflammatory Response Pathway; Intestines; Investigation; Linear Models; Logistic Regressions; Matched Case-Control Study; Medical; Modeling; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Norovirus; Oral; Outcome; Pathogenesis; Patient Care; Pattern; Physicians; Population Study; Predisposition; Prevention; Prevention strategy; Production; Prophylactic treatment; Public Health; Research; Research Personnel; Sampling; Sanitation; Serum; Societies; Study models; Symptoms; Techniques; Testing; Therapeutic; Time; Training; Trees; United States; Universities; Vaccines; Validation; Viral; Viral Gastroenteritis; Virus; Virus Diseases; Virus Shedding; Work; Writing; adaptive immunity; base; career; career development; chemokine; clinically relevant; cytokine; improved; innovation; insight; medical schools; non-genetic; pathogen; predictive modeling; programs; public health relevance; response; skills; tool; trend; vaccine candidate; vaccine development; viral detection; volunteer

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.

描述(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，占全球流行性胃肠炎的50%以上。然而，对人类新城疫免疫学的了解有限，部分原因是缺乏细胞培养系统。因此，我们建议使用实验性人类NOV挑战研究的血清样本来研究NOV的先天免疫反应。初步研究表明，个体对NOV的先天免疫反应有所不同，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、病毒滴度和病毒脱落持续时间的差异是由于促炎细胞因子的产生增加所致。对宿主防御机制的更好理解将有助于开发更好的预防措施(例如疫苗)、预测算法和公共卫生预防战略。这项研究的目的是阐明人类对NOV挑战的先天免疫反应的差异。为了达到这一目标，我们建议：1.确定细胞因子和趋化因子预测11月攻击后的感染状态；2.确定细胞因子和趋化因子预测感染志愿者的症状、病毒滴度峰值和病毒脱落持续时间。这位奖学金申请者立志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，以便改进预防和治疗工作。根据这一奖学金，她将通过流行病学医学博士学位获得严格的免疫学和流行病学方法学基础。这种培训对于解决拟议的研究问题、培养作为独立调查员所需的技能以及实现她的长期职业目标至关重要。这一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门知识；2.培养实验设计方面的高度熟练程度；3.在临床医学方面建立坚实的基础；4.接触各种临床学科和正在进行的人口研究；5.积极了解人类免疫学、流行病学和临床医学的趋势和发展；6.在科学写作和口头陈述方面培养卓越能力；以及7.积极寻求职业发展机会。在资助期开始时，申请者将已经在埃默里大学医学院完成了两年的医学研究，并在流行病学博士课程中学习了一年。这项拟议的研究试图了解人类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素。 病毒脱落的可能性。了解先天免疫反应对于推动NOV疗法的发展、创建监测工具和预测临床结果至关重要。