TONSILS: AN UNRECOGNIZED ROLE IN INFLUENZA VIRUS EVOLUTION

扁桃体：流感病毒进化中一个未被认识的角色

基本信息

批准号：
10676857
负责人：
Faten Abdelaal Okda
金额：
$ 10万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-04 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10676857
关键词：
Affect Animal Model Animals Anterior Antibodies Antibody Response Antibody titer measurement B-Lymphocytes Birds Cecum Cells Child Chiroptera Clinical Clinical Research Data Disease Outbreaks Ecology Education Ensure Enteral Environment Epidemic Epithelial Cells Epithelium Equipment Evolution Exhibits Family suidae Ferrets Future Genetic Engineering Goals HIV Hand Human Immune response Immunity Immunization Immunohistochemistry In Vitro Individual Infection Infection prevention Infiltration Inflammatory Institution Integration Host Factors Laboratories Link Mammals Measures Medical History Mentors Modeling Monitor Morphology Mutation Nasopharynx Oral cavity Organ Oropharyngeal Outcome Palatine Tonsil Pathogenesis Pathogenicity Patients Persons Phase Play Polyomavirus Porcine Reproductive and Respiratory Syndrome Predisposition Prevalence Procedures Protocols documentation Public Health Reagent Reporting Resources Role Saint Jude Children&apos s Research Hospital Salivary immunoglobulin A Sampling Sequence Analysis Serum Severities Severity of illness Sialic Acids Site Soft Palate Specificity Spottings Structure of germinal center of lymph node System T-Lymphocyte Time Tissues Tonsil Tonsillar Tissue Tonsillectomy Training Vaccination Vaccines Viral Viral Pathogenesis Virus Virus Diseases Virus Replication age group antigen processing chemokine cytokine disorder control epidemic virus fitness future pandemic improved influenza infection influenza virus strain influenza virus vaccine influenzavirus insight live attenuated influenza vaccine loss of function lymphoid organ pandemic disease pandemic potential preference prevent prevent pandemics receptor binding research clinical testing respiratory response sialic acid receptor transmission process viral fitness viral transmission

项目摘要

Identifying the host factors that contribute to influenza virus (IV) pathogenesis are critical for disease control and preventing pandemics. The tonsils comprise 2 lymphoid organs located in the nasopharynx of mammals and in the cecum of birds, in which IVs are enteric. The tonsils are an initial site of various viral infections and transmission, but their role in IV pathogenesis is unclear. My proposed studies will provide new insights on how the tonsils contribute to IV pathogenesis, immune responses, and adaptation by identifying the role of the tonsils in IV pathogenesis, performing tonsillectomy in ferrets to recapitulate the heterogeneous responses to IV infection severity and vaccination in subpopulations of humans with/without tonsils, and exploring the role of the tonsils in IV adaptation. My recent study demonstrated that human tonsillar epithelial cells (HTECs) are susceptible to IV infections, with effective replication of different IV subtypes in vitro. I will expand upon these findings by performing time-intensive monitoring of IV infection dynamics and distribution in the tonsils of ferrets. I collected and analyzed human tonsillectomy data over the last 60 years in the US and found that the percentage of human subpopulations with tonsillectomies is high in different age groups. The prevalence, disease severity, and level of immunity of IV infections in these subpopulations are unknown, and the role of the tonsils in epidemic or pandemic spread of IVs is undetermined. I previously found that HTECs induce chemokine and cytokine release during IV infection. Previous clinical studies reported no differences in salivary IgA immune responses to IV live attenuated vaccine in individuals before and after tonsillectomy, but these studies were limited by low patient numbers and confounded by original antigenic sin. I will use ferrets to ascertain how tonsillectomy affects immunity resulting from the IV infection and vaccine. I will measure the quantity and quality of antibody responses after infection and/or immunization and compare T- cell and B-cell activity in ferrets with and without tonsils. The soft palate is an important site of IV adaptation, extending downward in the oral cavity and passing anterior and posterior to the tonsils. The replicative fitness of IVs in tonsillar tissues may induce rapid selection, ostensibly preventing infection and reducing their pandemic potential. Therefore, I propose to verify the role of the tonsils in IV adaptation a tissue not typically sampled in animal models of IV and investigate the extent of different human IV replication in the tonsils. Acquiring mutations and switching receptor-binding specificity between avian and human sialic acid (SA) preferences are key for IV transmission and adaptation. I previously found that both human and avian tonsil epithelial cells are rich in both human α2,6 and avian α2,3–linked SA receptors and support IV replication. I will use genetically engineered IVs with altered SA preferences to conduct transmission studies and analyze the viral fitness within the tonsils that may select for transmissible IVs more rapidly than the soft palate by using a loss-of-function approach. The mentored phase of this proposal will occur at St. Jude Children Research Hospital under the auspices of Richard Webby and will elucidate the role of the tonsils in IV pathogenesis and immune responses to infection. The independent phase will focus on immune responses to IV vaccines and IV adaptation. The institutional resources, academic environment, and educational opportunities outlined in my proposal will ensure my successful transition to independence.

确定有助于影响病毒（IV）发病机理的宿主因素对于疾病控制和预防至关重要大流行。扁桃体包含2个位于哺乳动物鼻咽和鸟类中的淋巴机器人，在促进了IV。扁桃体是各种病毒感染和传播的初始部位，但它们在IV中的作用发病机理尚不清楚。我提出的研究将提供有关扁桃体如何对IV发病机理贡献的新见解，免疫反应和通过识别扁桃体在静脉发病机理中的作用，进行扁桃体切除术来适应雪貂概括人类亚群中对静脉注射严重程度和疫苗接种的异质反应使用/没有扁桃体，并探索扁桃体在IV适应中的作用。我最近的研究表明人类扁桃体上皮细胞（HTEC）易受IV感染的影响，并有效地复制了不同的IV亚型。我将通过对IV感染动态和分布的时间密集型监测来扩展这些发现雪貂的扁桃体。我在过去60年中收集并分析了人类扁桃体切除术数据，发现在不同年龄组中，人类扁桃体切除术的亚群百分比很高。患病率，疾病的严重程度，这些亚群中静脉感染免疫的水平尚不清楚，扁桃体在流行病或 IVS的大流行不确定。我先前发现HTEC在静脉注射期间诱导趋化因子和细胞因子释放感染。先前的临床研究报告说，唾液IgA免疫回应对静脉注射疫苗没有差异在扁桃体切除术前后的个体中原始抗原罪。我将使用雪貂来确定扁桃体切除术如何影响因静脉感染而产生的免疫力疫苗。我将测量感染和/或免疫后抗体反应的数量和质量，并比较T- 带有和不含扁桃体的雪貂中的细胞和B细胞活性。柔软的口感是IV适应的重要部位，延伸向下口腔，并在扁桃体的前方和后方。 IV在扁桃体组织中的复制适应性可能引起快速选择，表面上可以防止感染并降低其大流行潜力。因此，我建议验证扁桃体在IV适应中的作用扁桃体中不同的人类静脉复制。获取突变并切换接收器结合特异性鸟类和人类唾液酸（SA）偏好是静脉传播和适应的关键。我以前发现两个人和禽扁桃体上皮细胞富含人α2,6和禽α2,3连接的SA受体，并支持IV复制。我将使用具有变化的SA偏好的一般设计的IV进行传输研究并分析病毒扁桃体内的适合度比软性损失可以更快地选择可传播IV的扁桃体。方法。该提案的修改阶段将在圣裘德儿童研究医院发生理查德·韦伯（Richard Webby），将阐明扁桃体在静脉内发病机理中的作用，并免疫复杂对感染的作用。这独立阶段将集中于对IV疫苗和IV适应的免疫调查。机构资源，学术我的提案中概述的环境和教育机会将确保我成功过渡到独立性。