Regulation of mucosal immunity to respiratory viruses by Tpl2

Tpl2对呼吸道病毒粘膜免疫的调节

• 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
• 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

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.

摘要 季节性流感流行在全球每年导致300 - 500万人严重患病和30万-50万人死亡 年[1]。在美国，仅季节性流感的财政负担每年就接近900亿美元[2]。 季节性流感病毒会迅速变异和进化，需要每年重新制定流感疫苗- 电影，这仅仅是对即将到来的流行菌株的预测。流感疫苗的效力差别很大 从大约10-60%; 2017-2018年流感季节特别严重，疫苗接种率低 有效性强调了改进流感疫苗策略的迫切需要。通用流感疫苗 理论上可以提供有效和持久的保护，防止多种流感病毒， 第一个是NIAID [1]。已确定的改进流感疫苗的步骤包括探索将 佐剂和改变给药途径，以最大限度地提高粘膜先天免疫应答， 影响免疫力[1]。宿主编码的干扰素（IFN）是介导先天性 保护以及调节对病毒的适应性免疫应答。III型干扰素（IFNλ）现在已经出现， 被认为是流感病毒感染期间产生的主要IFN，但信息有限， 关于调节IFNλ表达的宿主途径的信息。缺乏这样的知识是一个障碍，以改善- 制定疫苗战略，以控制病毒感染和易感人群的传播。我们最近 表明宿主编码的丝氨酸-苏氨酸激酶Tp 12可增强IFNλ的产生和宿主的保护作用。 预防流感病毒感染。因此，本申请的目的是更好地了解- 研究Tp 12如何协调对流感病毒的先天免疫应答。这将在两个目标中进行审查。 在目的1中，病毒诱导Tp 12激酶活性和细胞内信号传导途径的机制被阐明。 促进IFNλ和放大抗病毒IFN应答。在目标2中，上皮细胞-内源性 将阐明Tp 12在流感病毒感染期间的功能。实验方法将利用初级 鼠肺上皮细胞，遗传改变的小鼠品系，包括肺上皮细胞特异性消融， Tp 12和无偏全基因组转录组分析。拟议研究的结果将导致 更全面地了解肺上皮细胞如何对呼吸道感染产生保护性粘膜反应， 病毒从这些研究中获得的信息将有助于改善呼吸道病毒的疫苗策略 并可能转化为其他嗜粘液性感染性疾病，其中IFNλ在 免疫保护