The role of autophagy in innate anti-viral immunity in Drosophila

自噬在果蝇先天抗病毒免疫中的作用

• 批准号: 8601288
• 负责人: Sara Cherry
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8601288
• 关键词: Adult; Antiviral Agents; Antiviral Response; Arboviruses; Arthropods; Attenuated; Autophagocytosis; Binding; Biological Assay; Biological Models; Capsid; Capsid Proteins; Cell membrane; Cells; Data; Degradation Pathway; Drosophila genus; Employee Strikes; Exhibits; Funding; Genetic; Health; Human; Human Virus; Immune; Immune response; Immune system; Immunity; In Vitro; Infection; Insect Vectors; Insecta; Knowledge; Link; Mammalian Cell; Mammals; Membrane Glycoproteins; Molecular; Natural Immunity; Nobel Prize; Nutrient; Pathway interactions; Pattern; Pattern recognition receptor; Phenotype; Play; Production; RNA Interference; Receptor Signaling; Research; Role; Signal Pathway; Signal Transduction; Staging; System; Testing; Therapeutic; Therapeutic Intervention; Toll-Like Receptor Pathway; Toll-like receptors; Translations; Vesicular stomatitis Indiana virus; Viral; Viral Genome; Virus; Virus Diseases; Work; Yeasts; antimicrobial; attenuation; base; combat; disease transmission; fly; human disease; novel; novel strategies; pathogen; programs; public health relevance; receptor; response; tool; vector; vector mosquito

DESCRIPTION (provided by applicant): 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 both in the insect vector and 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. Thus, discoveries in fruit flies may have profound impacts on human health by identifying novel approaches to interfere with disease transmission in vector species and revealing conserved immune pathways in mammals. One essential pathway that restricts the human arbovirus Vesicular Stomatitis virus (VSV) in Drosophila is autophagy, an ancient intracellular degradative program evolutionarily conserved from yeast to humans. Based on preliminary data, this response depends on the interaction between VSV and a previously uncharacterized Toll receptor, Toll-7; however, the downstream pathways and global significance of Toll receptors remain unknown. The long-term objective of this application is to define the molecular mechanisms by which Drosophila recognizes viral infections to induce protective antiviral autophagy. Because these pathways share a number of molecular and functional similarities to mammalian TLR pathways, and increasing in vitro data suggest that TLRs activate autophagy during a variety of infections, the proposed research also has the potential to extend our understanding of the mechanisms that link innate immunity to autophagy in mammals. As such, this application proposes three specific aims: (1) elucidate the mechanism by which virus is targeted by autophagy; (2) identify the role of Toll receptors in antiviral autophagy and defense; and (3) explore the signaling pathways that link virus recognition to autophagy in flies and mammals. These studies will expand our understanding of the molecular mechanisms underlying antiviral autophagy in flies, as well as conserved autophagy-inducing pathways likely downstream of TLR signaling in mammals. Moreover, this research opens a previously unappreciated and unexplored realm of Toll receptors in immunity, which may serve as effective targets for novel vector-based antiviral therapeutics given their conservation in other insects.

描述（由申请人提供）：先天免疫是针对病原体的第一道防线，并且是从昆虫到人类的高度保守的。尽管已经阐明了先天免疫系统的许多关键方面，但我们对限制昆虫载体和哺乳动物宿主的途径的途径存在根本差距。重要的是，对这些机制的分子理解对于克服缺乏有效的抗病毒疗法并打击人类疾病至关重要。果蝇免疫反应与载体昆虫的免疫反应高度同源，并与哺乳动物先天免疫具有惊人的相似性。因此，通过鉴定出干扰载体物种中疾病传播并揭示哺乳动物中保守的免疫途径的新方法，可以通过识别新的方法来对人类健康产生深远的影响。限制果蝇中人弧病毒囊泡病毒病毒（VSV）的一种必不可少的途径是自噬，这是一种古老的细胞内降解程序，从酵母到人类。基于初步数据，此响应取决于VSV与先前未表征的收费受体Toll-7之间的相互作用。但是，收费受体的下游途径和全球意义仍然未知。该应用的长期目的是定义果蝇识别病毒感染以诱导保护性抗病毒药自噬的分子机制。由于这些途径与哺乳动物TLR途径具有许多分子和功能相似性，并且增加体外数据表明TLR在多种感染过程中激活了自噬，因此拟议的研究也有可能扩展我们对哺乳动物中自动噬菌体与自噬联系起来的机制。因此，该应用提出了三个特定目的：（1）阐明病毒靶向自噬的机制； （2）确定收费受体在抗病毒自噬和防御中的作用； （3）探索将病毒识别与苍蝇和哺乳动物自噬联系起来的信号传导途径。这些研究将扩展我们对蝇中抗病毒自噬的分子机制的理解，以及哺乳动物中TLR信号传导下游的保守自噬诱导途径。此外，这项研究开辟了以前未经批准的和未开发的免疫受体领域，鉴于它们在其他昆虫中的保存鉴于它们可以作为新型基于矢量的抗病毒疗法的有效靶标。