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

• 批准号: 10673509
• 负责人: Sara Cherry
• 金额: $ 24.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/10673509
• 关键词: Address; Agonist; Antigens; Antiviral Agents; Antiviral Response; Arbovirus Infections; Autophagocytosis; Biochemical; Biological; 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; Orthobunyavirus; 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; arthropod-borne; 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

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 先天免疫是针对病原体的第一道防线，从昆虫到高度保守 人类。尽管已经阐明了先天免疫系统的许多关键方面，但存在根本的差距 在我们了解限制了在各种靶向组织中限制节肢动物传播病毒感染的途径 在哺乳动物宿主感染期间感染。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打击人类疾病至关重要。 果蝇免疫反应与载体昆虫的反应高度同源，并共享引人注目的 与哺乳动物先天免疫的相似之处。使用果蝇系统，我们以前发现 果蝇模式识别受体感受到新兴的Bunyavirus Rift Valley Fever病毒（RVFV） （PRR），Toll-7，它激活抗病毒自噬，并且在哺乳动物细胞中保守。我们发现 TLR2依赖性抗病毒自噬可以控制某些细胞类型的RVFV，而在其他细胞中则可以控制 TLR2导致细胞死亡。此外，我们发现自噬的药理学激活对 哺乳动物原发性神经元中的RVFV，表明该途径可能是用于抗病毒药保护的。 由于PRR途径的组织特异性信号传导的特征很差，因此我们筛选了PRR激动剂的面板 对于那些可以阻止神经元和非神经元细胞中RVFV感染的人。我们确定了两个 抗病毒弹药的类别。首先，我们将两种细胞类型的TLR2激动剂确定为抗病毒。自从 自噬的药理学激活可以保护原发性哺乳动物神经元免受感染，我们建议 可以利用TLR2激活来捍卫神经元免受脑病病毒的侵害。其次，我们确定了 Dectin-1激动剂是神经元中特别探索的抗病毒剂。因此，长期 拟议的研究的目的是了解病毒感染的分子机制 被先天的途径感知和控制 包括神经元在内的各种细胞类型的防御。为了实现这些目标，本申请提出了两个 具体目的：（1）确定TLR2感知RVFV的机制，导致各种结果， 自噬或细胞死亡； （2）探索可以控制成熟哺乳动物的Bunyavirus的PRR途径 神经元。