Regulation of mucosal immunity to respiratory viruses by Tpl2

Tpl2对呼吸道病毒粘膜免疫的调节

基本信息

批准号：
9809582
负责人：
Wendy T Watford
金额：
$ 22.63万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-08 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9809582
关键词：
Ablation Address Adjuvant Antiviral Agents Antiviral Response Bone Marrow Cessation of life Chickens Chimera organism Communicable Diseases Data Development Epithelial Cells Feedback Financial Hardship Funding Mechanisms Gastrointestinal tract structure Genes Goals Health Host resistance Human ImProv Immune response Influenza Influenza A virus Innate Immune Response Interferon Type I Interferon-alpha Interferons Knowledge Laboratory Research Lung MAP3K8 gene Mediating Molecular Morbidity - disease rate Mouse Strains Mucosal Immunity Mucous Membrane Mus Mutate Mutation National Institute of Allergy and Infectious Disease Natural Immunity Outcome Pathway interactions Phosphotransferases Population Production Protein-Serine-Threonine Kinases Proteins Public Health Regulation Research Respiratory Mucosa Respiratory System Role Route Seasons Signal Pathway Signal Transduction Site Surface Testing Tissues Translating United States Vaccines Virus Virus Diseases Virus Replication adaptive immune response adaptive immunity design egg genome-wide immunoregulation improved in vivo influenza epidemic influenza virus vaccine influenzavirus mortality novel respiratory respiratory virus response seasonal influenza socioeconomics transcriptomics universal influenza vaccine urogenital tract vaccine development vaccine efficacy viral transmission

项目摘要

Abstract Seasonal influenza epidemics result in 3-5 million severe illnesses and 300,000-500,000 deaths globally each year [1]. In the United States, the financial burden of seasonal influenza alone is nearly $90 billion annually [2]. Seasonal influenza viruses mutate and evolve rapidly necessitating the annual reformulation of influenza vac- cines, which are merely predictions to the upcoming circulating strains. Influenza vaccine efficacies vary widely from approximately 10-60%; the 2017-2018 influenza season has been particularly severe, and low vaccine efficacy underscores the critical need for improved influenza vaccine strategies. A universal influenza vaccine would theoretically provide efficacious and durable protection against multiple influenza viruses and is a top priority of the NIAID [1]. Identified steps to improving influenza vaccines include exploring the incorporation of adjuvants and altering the route of administration to maximize mucosal innate immune responses that subse- quently influence adaptive immunity [1]. Host-encoded interferons (IFNs) are critical factors that mediate innate protection as well as modulate the adaptive immune response to viruses. Type III IFNs (IFNλs) are now appre- ciated to be the predominant IFNs produced during influenza virus infection, however there is limited infor- mation about the host pathways that regulate IFNλ expression. Lack of such knowledge is a barrier to improv- ing vaccine strategies to control virus infections and transmission in susceptible populations. We recently demonstrated that the host-encoded serine-threonine kinase, Tpl2, enhances IFNλ production and host protec- tion against influenza virus infection. Therefore, the objective of this application is to gain a better understand- ing of how Tpl2 coordinates the innate immune response to influenza virus. This will be examined in two Aims. In Aim 1, the mechanisms by which viruses induce Tpl2 kinase activity and intracellular signaling pathways to promote IFNλ and amplify the anti-viral IFN response will be delineated. In Aim 2, the epithelial cell-intrinsic functions of Tpl2 during influenza virus infection will be elucidated. Experimental approaches will utilize primary murine lung epithelial cells, genetically altered mouse strains including lung epithelial cell-specific ablation of Tpl2, and unbiased genome-wide transcriptomic analysis. The results of the proposed studies will lead to a more complete understanding of how lung epithelial cells generate protective mucosal responses to respiratory viruses. Information obtained from these studies will help to improve vaccine strategies for respiratory viruses and can likely be translated to other mucosotropic infectious diseases where IFNλs have prominent roles in immunoprotection.

抽象的季节性流感流行在全球范围内导致 3-500 万人患重病，并导致 300,000-500,000 人死亡年[1]，在美国，每年仅季节性流感一项的经济负担就接近 900 亿美元[2]。季节性流感病毒会迅速突变和进化，因此需要每年重新配制流感疫苗。电影，这仅仅是对即将流行的流感疫苗功效的预测，差异很大。大约10-60%；2017-2018年流感季节特别严重，疫苗接种率低功效强调了改进流感疫苗策略的迫切需要。理论上可以针对多种流感病毒提供有效且持久的保护，是顶级的 NIAID 的优先事项 [1] 已确定的改进流感疫苗的步骤包括探索纳入佐剂并改变给药途径以最大化粘膜先天免疫反应，宿主编码的干扰素 (IFN) 是介导先天性免疫的关键因素。现在人们已经认识到，III 型干扰素 (IFNλ) 具有保护作用以及调节对病毒的适应性免疫反应。介导是流感病毒感染期间产生的主要干扰素，但是信息有限缺乏有关调节 IFNλ 表达的宿主途径的知识是改进的障碍。制定疫苗策略来控制病毒在易感人群中的感染和传播。证明宿主编码的丝氨酸-苏氨酸激酶 Tpl2 增强 IFNλ 的产生并保护宿主因此，本应用的目的是更好地了解流感病毒感染。 Tpl2 如何协调对流感病毒的先天免疫反应这将在两个目标中进行研究。在目标 1 中，病毒诱导 Tpl2 激酶活性的机制和细胞内信号通路促进 IFNλ 并放大抗病毒 IFN 反应将在目标 2 中描述，即上皮细胞固有的。将利用主要实验方法阐明 Tpl2 在流感病毒感染期间的功能。小鼠肺上皮细胞，遗传小鼠品系，包括肺上皮细胞特异性消融 Tpl2和无偏见的全基因组转录组分析所提出的研究结果将导致一个结果。更全面地了解肺上皮细胞如何对呼吸道产生保护性粘膜反应从这些研究中获得的信息将有助于改进呼吸道病毒的疫苗策略。并且可能会转化为其他亲粘膜感染性疾病，其中 IFNλ 在其中发挥着重要作用免疫保护。