Immune Mechansims of Rotavirus Protection & Clearance

轮状病毒保护的免疫机制

• 批准号: 6340149
• 负责人: SARAH E BLUTT
• 金额: $ 4.02万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-25 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6340149
• 关键词: B lymphocyte; Rotavirus; T lymphocyte; cellular immunity; flow cytometry; laboratory mouse; leukocyte activation /transformation; microorganism immunology; rotavirus vaccines; vaccine development

Rotavirus is the leading cause of severe gastroenteritis in young children worldwide. A vaccine to prevent a rotavirus infection would prevent over 500,000 deaths/year in developing countries and save the United States over $1 billion a year in health care costs, but recently, the only licensed vaccine was withdrawn due to associated side effects. Protection from rotavirus infection and resulting disease is dependent on the initiation and maintenance of an immunological response. The goal of this application is to understand and compare the difference in protective immunological responses induced by a live rotavirus infection and by a non-replicating subunit vaccine (VLPs). The immunological response to both live rotavirus infection and a VLP vaccine will be differentiated by many factors including the time of response, the type of cells that control the response, and establishment of immunological memory. In mice, rotavirus infection and VLP vaccination can induce sterilizing immunity. The exact mechanisms through which rotavirus and VLPs induce sterilizing immunity in the mouse have not been elicited. I hypothesize that (i) clearance of and sterilizing immunity established by a primary rotavirus infection occurs predominately as a result of T cell independent B lymphocyte activation, and (ii) VLP vaccination will cause sterilizing immunity through T cell dependent B lymphocyte activation. To test this hypothesis, flow cytometry will be used to identify, quantitate, and functionally characterize activated lymphocyte subsets during clearance of a primary rotavirus infection, after vaccination with VLPs, and after a rotavirus challenge of previously infected or VLP vaccinated mice. These will be the first studies to systematically identify and compare subsets of activated lymphocytes between a live infected and VLP vaccinated animal and correlating these responses with protection from infection. Understanding the mechanisms of how rotavirus and vaccination with VLPs activate the immune system to induce sterilizing immunity will aid in better vaccine design and may identify benchmarks for testing potential vaccine effectiveness in humans.

轮状病毒是全球幼儿严重胃肠炎的主要原因。预防轮状病毒感染的疫苗将在发展中国家每年防止超过500，000人死亡，并每年为美国节省超过10亿美元的医疗保健费用，但最近，由于相关的副作用，唯一获得许可的疫苗被撤回。对轮状病毒感染和由此产生的疾病的保护依赖于免疫应答的启动和维持。本申请的目的是了解和比较由活轮状病毒感染和由非复制型亚单位疫苗（VLP）诱导的保护性免疫应答的差异。对活轮状病毒感染和VLP疫苗的免疫应答将通过许多因素区分，包括应答时间、控制应答的细胞类型和免疫记忆的建立。在小鼠中，轮状病毒感染和VLP疫苗接种可诱导杀菌免疫。轮状病毒和VLP在小鼠中诱导绝育免疫的确切机制尚未得到证实。我假设（i）由原发轮状病毒感染建立的清除和杀菌免疫主要是T细胞非依赖性B淋巴细胞活化的结果，（ii）VLP疫苗接种将通过T细胞依赖性B淋巴细胞活化引起杀菌免疫。为了检验这一假设，将使用流式细胞术在原发性轮状病毒感染清除期间、VLP接种后以及先前感染或VLP接种的小鼠轮状病毒攻毒后鉴定、定量和功能表征活化的淋巴细胞亚群。这些将是第一个研究，以系统地确定和比较活化淋巴细胞的亚群之间的活感染和VLP疫苗接种的动物，并将这些反应与保护免受感染。了解轮状病毒和VLP疫苗接种如何激活免疫系统以诱导杀菌免疫的机制将有助于更好的疫苗设计，并可能确定用于测试人类潜在疫苗有效性的基准。