A novel virus-derived adjuvant

描述(申请人提供)：大多数具有临床意义的病毒编码干扰I型干扰素(干扰素)途径的拮抗剂，从而促进感染和病理的建立。在I型干扰素途径拮抗剂存在的情况下，启动抗病毒免疫反应的机制尚未确定。这些机制可能代表了将病理学降至最低的新靶点和/或可能解释了常见病毒病原体的不同临床结果。我们的小组发现，特殊缺陷形式的病毒基因组(DVGs)，直到最近还被认为是体外病毒复制的副现象，是触发宿主反应的强大危险信号，即使在病毒编码的拮抗剂存在的情况下也是如此。此外，我们还证明，在感染小鼠呼吸道病原体仙台病毒(SeV)或小鼠适应的甲型流感病毒(IAV)期间，DVGs在肺内的自然积累与抗病毒反应的开始相关，并且主要抗病毒细胞因子干扰素β的产生仅限于DVG阳性的肺细胞部分。重要的是，分析感染了肺炎的儿童的呼吸道分泌物 与SeV相关的人类呼吸道合胞病毒(RSV)表明，DVGs的检测也与人类I型IFN转录增强相关。值得注意的是，在感染了各种病毒的患者的血清中发现了DVGs，我们的数据首次证明了在急性感染期间产生的DVGs促进了体内免疫反应的开始。因此，我们假设在阻断I型干扰素途径的病毒感染中，DVGs对于诱导抗病毒反应是必不可少的，它们的存在决定了感染的临床结果。这一新应用的目标是(I)确定DVGs强大的免疫刺激能力的独特分子机制，(Ii)确定DVGs如何在体内启动免疫反应，以及(Iii)评估RSV DVGs在人类肺部病毒致病中的作用。总体而言，这些研究将促进我们对病毒感染的先天免疫反应启动机制的理解，并可能对新的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.