The role of pattern recognition and autophagy in innate anti-bunyaviral immunity

摘要 先天免疫是抵御病原体的第一道防线，从昆虫到 人类。虽然先天免疫系统的许多关键方面已被阐明，但仍存在一个根本的差距。 在我们对限制节肢动物传播的病毒感染途径的了解中，不同的靶组织 都是在哺乳动物宿主感染期间感染的。重要的是，对这些的分子理解 机制对于克服缺乏有效的抗病毒疗法和抗击人类疾病至关重要。 果蝇的免疫反应与媒介昆虫的免疫反应高度同源，而且有惊人的共同之处 与哺乳动物的先天免疫相似。使用果蝇系统，我们之前发现 新出现的布尼亚病毒裂谷热病毒(RVFV)是由果蝇模式识别受体感知的 (PRR)，Toll-7，激活抗病毒自噬，这在哺乳动物细胞中是保守的。我们发现 依赖TLR2的抗病毒自噬可以在某些细胞类型中控制RVFV，而在另一些细胞中 TLR2导致细胞死亡。此外，我们还发现，自噬的药理激活对 RVFV在哺乳动物初级神经元中的表达，表明这一途径可能被用于抗病毒保护。 由于PRR通路的组织特异性信号特征不佳，我们筛选了一组PRR激动剂 对于那些可以同时阻断神经元和非神经元细胞中RVFV感染的药物。我们确认了两个 抗病毒PAMP的类别。首先，我们确定TLR2激动剂在两种细胞类型中都是抗病毒的。自.以来 我们认为，药物激活自噬可以保护原代哺乳动物神经元免受感染。 TLR2的激活可能被用来保护神经元免受脑炎病毒的攻击。第二，我们确定了 Dectin-1激动剂作为神经元中的特异性抗病毒药物将得到进一步的探索。因此，从长远来看， 这项拟议研究的目的是了解病毒感染的分子机制 由先天通路感知和控制，以及如何利用这一途径来诱导保护性 包括神经元在内的多种细胞类型的防御。为了实现这些目标，该应用程序提出了两个 具体目标：(1)确定TLR2感知RVFV导致不同结果的机制， 自噬或细胞死亡；以及(2)探索在成熟哺乳动物中控制布尼亚病毒的PRR途径。 神经元。

Summary Innate immunity is the first line of defense against pathogens and is highly conserved from insects to humans. While many key facets of the innate immune system have been elucidated, there is a fundamental gap in our knowledge of the pathways that restrict arthropod-borne viral infections in the diverse target tissues that are infected during the infection of the mammalian host. Importantly, a molecular understanding of these mechanisms is essential to overcome the lack of effective antiviral therapeutics and combat human disease. The Drosophila immune response is highly homologous to that of vector insects and additionally shares striking similarities with mammalian innate immunity. Using the Drosophila system, we previously found that the emerging bunyavirus Rift Valley Fever virus (RVFV) is sensed by the Drosophila Pattern recognition receptor (PRR), Toll-7, which activates antiviral autophagy and that this is conserved in mammalian cells. We found that TLR2-dependent antiviral autophagy can control RVFV in some cell types while in other cells engagement of TLR2 leads to cell death. Moreover, we found that pharmacological activation of autophagy is restrictive against RVFV in mammalian primary neurons, suggesting that this pathway may be harnessed for antiviral protection. Since tissue-specific signaling of PRR pathways are poorly characterized we screened a panel of PRR agonists for those that could block RVFV infection in neurons and in non-neuronal cells in parallel. We identified two classes of antiviral PAMPs. First, we identified TLR2 agonists as antiviral in both cell types. Since pharmacological activation of autophagy can protect primary mammalian neurons from infection, we suggest that TLR2 activation may be harnessed to defend neurons from encephalitic viruses. Second, we identified Dectin-1 agonists as specifically antiviral in neurons which will be further explored. Therefore, the long-term objective of the proposed research is to understand the molecular mechanisms by which viral infections are sensed and controlled by innate pathways and how this may be harnessed to induce protective defenses in diverse cell types including neurons. To accomplish these goals, this application proposes two specific aims: (1) to identify the mechanism by which RVFV is sensed by TLR2 leading to diverse outcomes, autophagy or cell death; and (2) explore the PRR pathways that can control bunyaviruses in mature mammalian neurons.