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）发病机制的宿主因素对于疾病控制和预防至关重要扁桃体由位于哺乳动物鼻咽部和鸟类盲肠中的 2 个淋巴器官组成。扁桃体是各种病毒感染和传播的起始部位，但它们在静脉注射中的作用。发病机制尚不清楚。我提出的研究将为扁桃体如何促进 IV 发病机制提供新的见解，通过确定扁桃体在 IV 发病机制中的作用、进行扁桃体切除术来进行免疫反应和适应雪貂重现人类亚群对 IV 感染严重程度和疫苗接种的异质反应有/没有扁桃体，并探索扁桃体在静脉注射适应中的作用。扁桃体上皮细胞（HTEC）对 IV 感染敏感，不同 IV 亚型在体外可有效复制。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。我收集并分析了美国过去 60 年的人类扁桃体切除术数据，发现不同年龄组中接受扁桃体切除术的人类亚群的比例较高。这些亚人群对 IV 感染的免疫力水平尚不清楚，扁桃体在流行病或流行病中的作用也不清楚。 IV 的大流行传播尚未确定。我之前发现 HTEC 在 IV 期间诱导趋化因子和细胞因子释放。先前的临床研究报告说，唾液 IgA 对 IV 减毒活疫苗的免疫反应没有差异。在扁桃体切除术之前和之后的个体中进行了研究，但这些研究受到患者数量少的限制，并且受到以下因素的干扰：我将使用雪貂来确定扁桃体切除术如何影响静脉注射感染和免疫系统。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- 有或没有扁桃体的雪貂的细胞和 B 细胞活性软腭是 IV 适应、延伸的重要部位。静脉注射在口腔中向下并穿过扁桃体的前部和后部。可能会引起快速选择，表面上预防感染并减少其大流行的可能性。验证扁桃体在 IV 适应中的作用（IV 动物模型中通常不会采样的组织）并调查其程度扁桃体中不同人类 IV 复制的获得突变和受体结合特异性的转换。我之前发现，鸟类和人类对唾液酸（SA）的偏好是静脉注射和适应的关键。禽类扁桃体上皮细胞富含人类α2,6和禽类α2,3连接的SA受体并支持IV复制。我将使用具有改变的 SA 偏好的基因工程 IV 来进行传播研究并分析病毒通过使用功能丧失，扁桃体内的适应性可能比软腭更快地选择可传播的 IV 该提案的指导阶段将在圣裘德儿童研究医院的赞助下进行。理查德·韦比（Richard Webby）将阐明扁桃体在 IV 发病机制和感染免疫反应中的作用。独立阶段将重点关注静脉注射疫苗的免疫反应和静脉注射适应。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。