Regulation of mucosal immunity to respiratory viruses by Tpl2

摘要 季节性流感疫情导致全球300-500万人患重病，30万-50万人死亡 年份[1]。在美国，仅季节性流感每年的经济负担就接近900亿美元[2]。 季节性流感病毒变异和进化迅速，需要每年重新配制流感疫苗。 电影，这仅仅是对即将到来的循环毒株的预测。流感疫苗的效力差异很大 从大约10%-60%；2017-2018年流感季节已经特别严重，疫苗接种率较低 有效性强调了改进流感疫苗战略的迫切需要。一种通用的流感疫苗 理论上对多种流感病毒提供有效和持久的保护，是最好的 NIAID的优先级[1]。改进流感疫苗的已确定步骤包括探索纳入 佐剂和改变给药途径，以最大限度地提高粘膜先天免疫反应，从而取代- 影响适应性免疫[1]。宿主编码的干扰素(IFN)是介导先天遗传的关键因素 保护以及调节对病毒的适应性免疫反应。III型IFN(干扰素λS)现已批准 被认为是流感病毒感染过程中产生的主要干扰素，但信息有限-- 关于调节干扰素λ表达的宿主途径的信息。缺乏这样的知识是提高- ING疫苗战略，以控制病毒感染和在易感人群中的传播。我们最近 研究表明，宿主编码的丝氨酸苏氨酸激酶TPL2可增强干扰素λ的产生和宿主的保护作用。 预防流感病毒感染。因此，这项申请的目的是为了更好地了解- Tpl2如何协调对流感病毒的先天免疫反应。这将从两个目标进行审查。 在目标1中，病毒诱导Tpl2激酶活性和细胞内信号通路的机制 促进干扰素λ和放大抗病毒干扰素应答将被描绘出来。在目标2中，上皮细胞-固有的 Tpl2在流感病毒感染过程中的作用将被阐明。试验性方法将利用主要 小鼠肺上皮细胞，转基因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产生对呼吸的保护性粘膜反应 病毒。从这些研究中获得的信息将有助于改进呼吸道病毒的疫苗策略 很可能被翻译成其他嗜黏膜传染病，其中干扰素λS在这些疾病中起着重要作用 免疫保护。

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.