Regulation of host cell inflammatory and maturation response through AdV DNAdete

描述（由申请人提供）：在目前的提案中，我们描述了细胞质DNA传感器的DNA识别如何协调炎症小体和I型干扰素（IRF3）激活的抗病毒级联反应。我们提出细胞质DNA传感器蛋白AIM2是激活这两个级联的关键。利用重组腺病毒载体感染巨噬细胞系或原代细胞，我们正在确定如何触发DNA传感机制信号激活IRF3 I型干扰素反应并影响这些抗原提呈细胞的成熟。基于初步数据，我们发现DNA传感器响应的重要下游靶标之一是接头蛋白STING。支持DNA传感器协同激活炎性小体/STING靶点的支架将被研究。目前的建议提出了AIM2的功能是平衡抗原呈递细胞抗病毒反应的假设。我们发现AIM2是一个干扰素诱导基因，也通过STAT1参与调节I型干扰素敏感性。我们提出AIM2/STAT1调节环功能来控制目标免疫前哨细胞的炎症/IFN敏感性。本提案中提出的研究是针对重组腺病毒载体的先天和适应性免疫反应的核心免疫识别反应途径。我们提出这些途径在免疫细胞中以一种特定的方式运作。从这些研究中获得的知识将有助于加强疫苗、基因治疗和抗癌治疗的应用，它们将有助于我们开发针对病毒感染和宿主DNA依赖性自身免疫性疾病的新疗法。

DESCRIPTION (provided by applicant): In the current proposal we are characterizing how DNA recognition by cytosolic DNA sensors coordinates activation of both the inflammasome and type I Interferon (IRF3) activated antiviral cascades. We are proposing the cytosolic DNA sensor protein AIM2 is pivotal to activation of both cascades. Using recombinant adenovirus vector infection of macrophage cell lines or primary cells, we are determining how triggering the DNA sensing machinery signals activation of the IRF3 type I interferon response and influences maturation of these antigen presenting cells. Based on preliminary data, we show that one of the essential downstream targets of the DNA sensor response is the adaptor protein STING. The scaffolds that support DNA sensor co-activation of inflammasome/STING targets will be examined. The current proposal presents the hypothesis that AIM2 is functioning to balance the antigen-presenting cell antiviral response. We have found that AIM2 which is an interferon inducible gene is also involved in regulating type I interferon sensitivity through STAT1. We are proposing an AIM2/STAT1 regulatory loop functions to control the inflammatory/IFN sensitivity of target immune sentinel cells. The studies presented in this proposal are targeting the immune recognition response pathways that are at the heart of the innate and adaptive immune response to recombinant adenovirus vectors. We are proposing these pathways are operating in a specific manner in immune cells. The knowledge gained from these studies will contribute to enhancing vaccine, gene therapy, and anticancer therapeutic applications and they will contribute to our ability to develop new treatments for viral infections and host DNA dependent autoimmune diseases. PUBLIC HEALTH RELEVANCE: Immune stimulating (is) DNA directly impacts immune function in DNA vaccines, DNA dependent autoimmune diseases and antiviral Immune responses. isDNA is a new and poorly understood area of the host (antiviral) immune response. In the current proposal we are investigating the DNA sensing networks triggered by rAdV infection of murine macrophages. Our research in this exciting and important area will contribute to immune modification strategies able to enhance the potency of DNA vaccines, enhance DNA vector gene transfer, or suppress DNA induced inflammatory diseases.