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

模式识别和自噬在先天性抗布尼亚病毒免疫中的作用

基本信息

批准号：
9917158
负责人：
Sara Cherry
金额：
$ 52.1万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-23 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917158
关键词：
Address Agonist Antigens Antiviral Agents Antiviral Response Arbovirus Infections Arthropods Autophagocytosis Biochemical Biological Bunyaviridae Cell Death Cells Cellular biology Data Drosophila genus Encephalitis Exhibits Genetic Polymorphism Genetic Transcription Goals Human Immune response Immunity Infection Infection Control Innate Immune Response Innate Immune System Insect Vectors Insecta Intervention Invaded Knowledge La Crosse virus Ligands Link Mammalian Cell Mammals Molecular Natural Immunity Nature Neuraxis Neuroglia Neurons Outcome Output Pathogenesis Pathway interactions Pattern Recognition Pattern recognition receptor Pharmacology Receptor Signaling Research Rift Valley fever virus Role Shapes Signal Pathway Signal Transduction System TLR2 gene Therapeutic Tissues Tropism Vaccines Virus Virus Diseases antiviral immunity beta-Glucans cell type combat dectin 1 dimer human disease insight novel novel strategies pathogen pathogenic virus programs receptor response screening tissue tropism treatment strategy

项目摘要

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.

概括先天免疫是对抗病原体的第一道防线，从昆虫到昆虫都高度保守。人类。虽然先天免疫系统的许多关键方面已被阐明，但仍存在根本性差距根据我们对限制不同靶组织中节肢动物传播的病毒感染的途径的了解，在哺乳动物宿主的感染过程中被感染。重要的是，对这些的分子理解机制对于克服有效抗病毒疗法的缺乏和对抗人类疾病至关重要。果蝇的免疫反应与媒介昆虫的免疫反应高度同源，并且还具有惊人的共同点与哺乳动物先天免疫相似。使用果蝇系统，我们之前发现新兴的布尼亚病毒裂谷热病毒（RVFV）被果蝇模式识别受体感知 (PRR)，Toll-7，可激活抗病毒自噬，并且这在哺乳动物细胞中是保守的。我们发现 TLR2 依赖性抗病毒自噬可以控制某些细胞类型中的 RVFV，而在其他细胞中则参与 TLR2 导致细胞死亡。此外，我们发现自噬的药理激活受到限制哺乳动物初级神经元中的 RVFV，表明该途径可用于抗病毒保护。由于 PRR 途径的组织特异性信号传导尚不清楚，我们筛选了一组 PRR 激动剂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。我们确定了两个抗病毒 PAMP 类别。首先，我们确定 TLR2 激动剂对两种细胞类型都具有抗病毒作用。自从我们建议，自噬的药理激活可以保护原代哺乳动物神经元免受感染 TLR2 激活可用于保护神经元免受脑炎病毒的侵害。其次，我们确定了 Dectin-1 激动剂在神经元中具有特异性抗病毒作用，这一点将得到进一步探索。因此，从长远来看拟议研究的目的是了解病毒感染的分子机制由先天途径感知和控制，以及如何利用它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，本申请提出了两个具体目标：(1) 确定 TLR2 感知 RVFV 并导致不同结果的机制，自噬或细胞死亡； (2)探索成熟哺乳动物中控制布尼亚病毒的PRR途径神经元。