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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.

确定导致流感病毒(IV)致病的宿主因素对于疾病控制和预防至关重要大流行。扁桃体由两个淋巴器官组成，分别位于哺乳动物的鼻咽和鸟类的盲肠。哪些静脉输液是肠道输液。扁桃体是各种病毒感染和传播的初始部位，但它们在IV中的作用发病机制尚不清楚。我提议的研究将为扁桃体如何在IV发病机制中发挥作用提供新的见解，免疫反应和适应通过确定扁桃体在IV发病机制中的作用，在雪貂总结人类亚群对IV感染严重性和疫苗接种的异质性反应有或没有扁桃体，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(HTECs)对IV感染很敏感，在体外可以有效复制不同的IV亚型。我将通过对IV感染动态和分布进行时间密集型监测来扩展这些发现雪貂的扁桃体。我收集和分析了过去60年来美国人类扁桃体切除术的数据，发现在不同年龄段的人群中，扁桃体摘除手术的比例很高。流行率，疾病严重程度，这些亚群中IV感染的免疫水平尚不清楚，扁桃体在流行或静脉输液的大流行传播尚不确定。我之前发现HTECs在静脉注射过程中会诱导趋化因子和细胞因子的释放感染。以前的临床研究报告对IV减毒活疫苗的唾液IgA免疫应答没有差异扁桃体切除前后的个体研究，但这些研究受到患者数量较少的限制，并受到原始性抗原罪。我将使用雪貂来确定扁桃体切除术如何影响IV感染产生的免疫力，以及疫苗。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- 有扁桃体和无扁桃体的雪貂的细胞和B细胞活性。软腭是IV适应的重要部位，延伸在口腔中向下，穿过扁桃体的前面和后面。扁桃体组织中静脉输注细胞的复制适合性可能导致快速选择，表面上预防感染并减少其大流行的可能性。因此，我建议验证扁桃体在IV适应中的作用，这是在IV动物模型中通常不取样的组织，并调查其程度在扁桃体中复制不同的人类IV病毒。获得突变和切换受体结合特异性禽类和人类唾液酸(SA)偏好是IV传播和适应的关键。我之前发现，人类禽类扁桃体上皮细胞富含人α-2，6和禽类α-2，3-SA受体，支持IV复制。我将使用改变了SA偏好的基因工程静脉输液来进行传播研究和病毒分析扁桃体内的适合度，通过使用功能丧失，可以比软腭部更快地选择可传播的静脉输液接近。该提案的指导阶段将在圣犹大儿童研究医院进行，由 Richard Webby，并将阐明扁桃体在IV发病机制和对感染的免疫反应中的作用。这个独立阶段将侧重于对IV疫苗的免疫反应和IV适应。机构资源、学术资源我的提案中概述的环境和教育机会将确保我成功地过渡到独立。