Role of TRAIL in immunity to influenza virus infections

描述(由申请人提供)：流感病毒不仅对流行性流感构成严重的公共卫生威胁，而且还因为高度致命的大流行爆发的威胁不断增加。原发流感病毒感染的清除在很大程度上被认为是通过流感特异性CD8T细胞介导的，CD8T细胞通过杀死感染流感的细胞来促进感染后的恢复。在历史上，负责消除流感感染的免疫机制依赖于穿孔素和FasL介导的反应，但最近的研究表明，CD8T细胞也可以通过TRAIL依赖的机制启动病毒感染细胞的凋亡。值得注意的是，我们对TRAIL参与流感病毒免疫反应的了解相当有限。因此，我们的长期目标是描述TRAIL在流感特异性免疫中的作用，着眼于设计保护性疫苗和激发针对这种重要人类病原体的有效免疫反应。我们的初步研究表明，在流感感染期间缺乏TRAIL表达会增加肺部病毒的滴度、发病率和疾病严重程度，并降低病毒特异性细胞毒作用。此外，流感病毒感染后，TRAIL和DR5(即TRAIL受体2)在野生型小鼠肺中的表达显著上调。TRAIL/DR5(即CD8T细胞/感染细胞)的表达与病毒清除和TRAIL+干扰素+流感特异性CD8 T细胞进入肺部有关，提示TRAIL/DR5的相互作用可能是流感病毒保护性免疫形成过程中不可或缺的一部分。因此，在这项建议中，我们将利用我们的流感病毒感染的小鼠模型和体外感染人肺细胞的模型来确定TRAIL表达在流感感染免疫中的作用。具体地说，我们将通过以下目标来解决这个问题：1)确定TRAIL缺乏是否会改变肺病毒清除、流感抗原载量和流感特异性CD8 T细胞反应；2)确定流感感染使肺细胞对TRAIL敏感的机制。这一建议不仅将增加我们对流感病毒感染的免疫反应的理解，还将阐明TRAIL表达/缺失如何改变流感病毒感染的毒力。这些知识不仅关系到我们对消除肺部病毒感染的机制的理解，而且关系到抗击流行病或大流行性流感暴发的方法的设计。项目简介：在流行和大流行流感期间，已知CD8 T细胞反应可以杀死感染流感的细胞，从而清除病毒并恢复。最近有报道称，CD8T细胞除利用穿孔素和FasL外，还可利用TRAIL介导对病毒感染细胞的杀伤作用。这个项目将增加我们对TRAIL在流感特异性免疫消除肺部病毒感染中的作用的了解，从而帮助我们设计应对流行病或大流行性流感爆发的战略。

DESCRIPTION (provided by applicant): Influenza virus represents a serious public health threat not only with regard to epidemic influenza but also due to the ever-increasing threat of highly virulent pandemic outbreaks. The clearance of primary influenza virus infections is largely thought to be mediated through influenza-specific CD8 T cells, which promote recovery from infection by the killing of influenza-infected cells. Historically, the immune mechanisms responsible for eliminating influenza infections were dependent on perforin and FasL-mediated responses, but recent studies have suggested that CD8 T cells can also trigger apoptosis in virus-infected cells via a TRAIL-dependent mechanism. Notably, our understanding of the involvement of TRAIL in immune responses to influenza-virus is quite limited. Therefore our long-term goal is to delineate the role of TRAIL in influenza-specific immunity with an eye toward the design of protective vaccines and elicitation of effective immune responses against this important human pathogen. Our initial studies have demonstrated that the absence of TRAIL expression during influenza infections increases pulmonary virus titers, morbidity and disease severity and decreases virus- specific cytotoxicity. Further TRAIL and DR5 (i.e. TRAIL receptor 2) expression are significantly upregulated in the lungs of wild type mice following influenza virus infections. This expression appears to correlate with virus elimination and the influx of TRAIL+IFN?+ influenza-specific CD8 T cells into the lungs, suggesting that TRAIL/DR5 (i.e. CD8 T cell/infected cell) interactions could be an integral part in the development of protective immunity to influenza virus. Therefore in this proposal we will utilize both our murine model of influenza virus infection and in vitro infection of human lung cells to determine what role TRAIL expression has in immunity to influenza infections. Specifically, we will address and resolve this question using the following Aims: 1) Determine if TRAIL deficiency alters pulmonary virus clearance, influenza antigen load, and influenza-specific CD8 T cell responses and 2) Determine the mechanism by which influenza infection sensitizes lung cells to TRAIL. This proposal will not only increase our understanding of the immune response to influenza virus infections but also elucidate how TRAIL expression/deficiency may alter the virulence of influenza virus infections. This knowledge will be relevant not only to our understanding of the mechanisms allowing elimination of virus infections in the lungs but also in the design of methods to combat epidemic or pandemic influenza outbreaks. Project Narrative: During epidemic and pandemic influenza, CD8 T cell responses are known to kill influenza-infected cells allowing clearance of the virus and recovery. Recently it has been reported that CD8 T cells can utilize TRAIL, in addition to perforin and FasL, to mediate the killing of virus infected cells. This project will increase our understanding of the role of TRAIL in influenza-specific immune elimination of virus infections of the lungs and therefore aid us in the design of strategies to combat epidemic or pandemic influenza outbreaks.