A novel virus-derived adjuvant

描述（由申请方提供）：大多数具有临床意义的病毒编码干扰I型干扰素（IFN）途径的拮抗剂，从而促进感染和病理学的建立。在I型IFN途径的拮抗剂存在下启动抗病毒免疫应答的机制尚未确定。这些机制可能代表新的目标，以尽量减少病理和/或可能解释不同的临床结果，以常见的病毒病原体。我们的研究小组确定，病毒基因组（DVG）的特殊缺陷形式，直到最近才被认为是体外病毒复制的附带现象，是触发宿主反应的有力危险信号，即使在病毒编码的拮抗剂存在的情况下。此外，我们证明了在小鼠呼吸道病原体仙台病毒（SeV）或小鼠适应性甲型流感病毒（IAV）感染期间DVG在肺中的自然积累与抗病毒反应的发生相关，并且主要抗病毒细胞因子IFN β的产生仅限于DVG阳性的肺细胞组分。重要的是，对感染了结核病的儿童的呼吸道分泌物的分析 SeV相关的人呼吸道合胞病毒（RSV）证明DVG的检测也与人I型IFN转录物的表达增强有关。值得注意的是，已经在感染各种病毒的患者的血清中鉴定了DVG，并且我们的数据首次证明了在急性感染期间产生的DVG促进体内免疫应答的发生。因此，我们假设DVG是必不可少的诱导的抗病毒反应的病毒感染，阻断I型IFN途径，它们的存在决定了感染的临床结果。本更新申请的目的是（i）鉴定控制DVG强免疫刺激能力的独特分子机制，（ii）确定DVG如何在体内启动免疫应答，以及（iii）评价RSV DVG在人肺中病毒发病机制中的作用。总的来说，这些研究将促进我们对病毒感染的先天免疫反应发病机制的理解，并可能对新型抗病毒治疗和预后工具的开发产生重大影响。

DESCRIPTION (provided by applicant): Most viruses of clinical relevance encode antagonists that interfere with the type I interferon (IFN) pathway thus promoting the establishment of the infection and pathology. The mechanisms involved in initiating the antiviral immune response in the presence of antagonists of the type I IFN pathway have not been identified. These mechanisms may represent novel targets to minimize pathology and/or may explain different clinical outcomes to common viral pathogens. Our group established that special defective forms of viral genomes (DVGs), which were until recently considered an epiphenomenon of in vitro virus replication, are potent danger signals that trigger the host response, even in the presence of virus-encoded antagonists. Moreover, we demonstrated that natural accumulation of DVGs in the lung during infection with the mouse respiratory pathogen Sendai virus (SeV) or with mouse-adapted influenza A virus (IAV) correlated with the onset of the antiviral response, and that production of the primary antiviral cytokine IFN beta was limited to the DVG-positive lung cellular fraction. Importantly, analysis of respiratory secretions from children infected with the SeV-related human respiratory syncytial virus (RSV) demonstrated that detection of DVGs is also associated with enhanced expression of transcripts for type I IFNs in humans. Notably, DVGs have been identified in the serum of patients infected with a variety of viruses and our data are the first demonstration that DVGs generated during an acute infection promote the onset of the immune response in vivo. We thus hypothesize that DVGs are essential for the induction of the antiviral response in infections with viruses that block the type I IFN pathway and that their presence determines the clinical outcome of the infection. The goals of this renewal application are (i) to identify unique molecular mechanisms governing the strong immunostimulatory ability of DVGs, (ii) to determine how do DVGs initiate the immune response in vivo, and (iii) to evaluate the role of RSV DVGs in the virus pathogenesis in the human lung. Overall, these studies will advance our understanding of the mechanisms involved in the onset of the innate immune response to virus infection and may have a significant impact on the development of novel antiviral treatments and prognostic tools.