Role of TRAIL in immunity to influenza virus infections

描述（由申请方提供）：流感病毒是一种严重的公共卫生威胁，不仅涉及流行性流感，而且由于高毒力大流行爆发的威胁不断增加。原发性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CD 8 T细胞介导的，其通过杀死流感感染的细胞促进从感染中恢复。历史上，负责消除流感感染的免疫机制依赖于穿孔素和FasL介导的应答，但最近的研究表明，CD 8 T细胞也可以通过TRAIL依赖性机制触发病毒感染细胞的凋亡。值得注意的是，我们对TRAIL参与流感病毒免疫应答的理解非常有限。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引发针对这种重要的人类病原体的有效免疫应答。我们的初步研究已经证明，流感感染期间TRAIL表达的缺乏增加了肺病毒滴度、发病率和疾病严重程度，并降低了病毒特异性细胞毒性。在流感病毒感染后，野生型小鼠的肺中进一步的TRAIL和DR 5（即TRAIL受体2）表达显著上调。这种表达似乎与病毒清除和TRAIL+IFN？+因此，TRAIL/DR 5（即CD 8 T细胞/感染的细胞）相互作用可能是流感病毒保护性免疫发展的组成部分。因此，在本提案中，我们将利用我们的流感病毒感染的鼠模型和人肺细胞的体外感染来确定TRAIL表达在对流感感染的免疫中的作用。具体而言，我们将使用以下目的来处理和解决这个问题：1）确定TRAIL缺乏是否改变肺病毒清除、流感抗原负荷和流感特异性CD 8 T细胞应答; 2）确定流感感染使肺细胞对TRAIL敏感的机制。这一提议不仅将增加我们对流感病毒感染的免疫应答的理解，而且还将阐明TRAIL表达/缺陷如何改变流感病毒感染的毒力。这些知识不仅有助于我们了解消除肺部病毒感染的机制，而且有助于设计防治流行性或大流行性流感爆发的方法。项目叙述：在流行性和大流行性流感期间，已知CD 8 T细胞应答杀死流感感染的细胞，从而允许病毒的清除和恢复。最近有报道称，除了穿孔素和FasL之外，CD 8 T细胞还可以利用TRAIL来介导对病毒感染细胞的杀伤。该项目将增加我们对TRAIL在流感特异性免疫消除肺部病毒感染中的作用的理解，从而帮助我们设计对抗流行性或大流行性流感爆发的策略。

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.