Autophagy in Antiviral Immunity

抗病毒免疫中的自噬

基本信息

批准号：
7981621
负责人：
AKIKO IWASAKI
金额：
$ 39.25万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7981621
关键词：
Ablation Agonist Animal Model Anti-Infective Agents Antigen Presentation Pathway Antigens Antiviral Agents Autophagocytosis Autophagosome Binding Biochemical Biological CD4 Positive T Lymphocytes Cells Cytosol DNA Virus Infections Data Dendritic Cells Endosomes Family Fibroblasts Foundations Generations Genes Genetic Genetic Transcription Herpesvirus 1 Homeostasis Immune response Immune system Immunity In Vitro Infection Interferon Type I Interferon-beta Interferons Life MHC Class II Genes Measures Mediating Mitochondria Molecular Mus Organelles Pathway interactions Peptides Play Population Process Proteins Proteomics RNA RNA Viruses Reactive Oxygen Species Receptor Signaling Reporting Role Scientific Advances and Accomplishments Signal Transduction Simplexvirus Starvation T cell response TLR7 gene Techniques Toll-like receptors Tretinoin Vaccine Design Vesicular stomatitis Indiana virus Viral Viral Antigens Virus Virus Diseases Work adaptive immunity antigen processing cell type combat cytokine design extracellular human TLR7 protein immunological intervention in vivo melanoma mouse model pathogen promoter public health relevance receptor response sensor tool

项目摘要

DESCRIPTION (provided by applicant): Autophagy is an ancient evolutionarily conserved pathway designed to maintain cellular homeostasis by degrading long-lived proteins and organelles in the cytosol. It is also used as a survival mechanism under starvation conditions. Recent studies demonstrated that autophagy is utilized by the cells of the innate and adaptive immune systems to combat viral infections. Innate recognition of viruses occurs via two distinct pathways. In professional viral sensors, the plasmacytoid dendritic cells (pDC), recognition of viruses occurs in the endosomes via Toll-like receptors (TLR) 7 and 9. Our recent work has demonstrated that autophagy plays a key role in recognizing signatures of viral infection in pDCs through TLR7. In contrast to pDCs, most other cell types of the body utilize cytosolic sensors of viral replication via RIG-I like receptor (RLR) family. Molecules involved in autophagy have been shown to block RLR signaling. In addition, recent reports indicate that autophagy delivers endogenous viral antigens to the MHC class II loading compartment, allowing activation of CD4 T cells. However, the relevance of such pathways during in vivo virus infection is unknown. In this application, we present preliminary data that reveal the requirement for Atg5, a key molecule required for formation of autophagosomes, in the transduction of signaling through TLR9 leading to the activation of type I IFN genes in pDCs upon herpes simplex virus (HSV; TLR9 agonist) infection. In addition, we show that autophagy negatively regulates RLR pathway in non-plasmacytoid dendritic cells upon vesicular stomatitis virus infection (VSV; RIG-I agonist). Finally, we demonstrate a key in vivo role for autophagy in the processing and presentation of various forms of antigens on MHC class II in dendritic cells upon HSV-1 infection. Building on these preliminary studies, we propose to examine the importance of autophagy in both innate and adaptive immune responses using a variety of molecular and cell biological techniques and using established mouse models of virus infection. In the first Aim, we will determine the mechanism by which Atg5 and/or autophagy mediates signaling through TLR9 upon HSV infection in pDCs through the use of molecular and cellular biological techniques. In the second Aim, we propose to determine how autophagy regulates RNA sensor activation upon VSV infection through proteomics and biochemical approaches. In the final Aim, we will interrogate how dendritic cells utilize autophagy for processing and presentation of extracellular viral antigens in vitro and in vivo in mice selectively deficient in autophagy within the dendritic cell populations. By providing basic understanding of how autophagy orchestrates the generation of innate and adaptive immunity against virus infections, these studies will help to establish important foundation with which to design vaccines and anti-infective measures against a variety of viral pathogens PUBLIC HEALTH RELEVANCE: While autophagy is an ancient evolutionarily conserved pathway designed to maintain cellular homeostasis by degrading long-lived proteins and organelles in the cytosol, recent studies from our group and others have revealed the role of autophagy in the immune system. In this application, we propose to examine the importance of autophagy in both innate and adaptive antiviral immune responses using well-established genetic, biochemical and cell biological tools as well as in vivo animal models of both RNA and DNA virus infections. The understanding gained from the proposed studies will not only provide scientific advances in how autophagy is utilized by the immune system, but also to help establish critical foundation with which to design immunological interventions and preventative measures against a wide variety of viral diseases.

描述（由申请人提供）：自噬是一种古老的进化保守途径，旨在通过在细胞质中降解长寿命的蛋白质和细胞器来维持细胞稳态。它也被用作饥饿条件下的生存机制。最近的研究表明，自动噬是由先天性和适应性免疫系统的细胞使用来对抗病毒感染。对病毒的先天识别是通过两种不同的途径发生的。在专业的病毒传感器中，血囊性树突状细胞（PDC），通过Toll样受体（TLR）7和9进行了对病毒的识别。我们最近的工作表明，自噬在识别PDC在PDC中通过TLR7识别病毒感染的关键作用。与PDC相反，大多数其他细胞类型的人体使用RIG-I像受体（RLR）家族使用病毒复制的胞质传感器。涉及自噬的分子已被证明可以阻止RLR信号传导。此外，最近的报告表明，自噬将内源性病毒抗原提供给MHC II类载荷室，从而激活CD4 T细胞。但是，在体内病毒感染期间这种途径的相关性尚不清楚。在本应用中，我们提供了初步数据，该数据揭示了对自体胶质体形成的ATG5的需求，这是通过TLR9的信号传导的转导，导致PDC在疱疹病毒（HSV; TLR9激动剂）感染的PDC中激活I型IFN基因。此外，我们表明自噬对囊泡孔炎病毒感染（VSV; rig-i agonist）进行了非质囊性树突状细胞中的RLR途径。最后，我们在HSV-1感染后，在树突状细胞中MHC II类中的各种形式的抗原处理和表现中，自噬在体内作用是自噬的关键作用。在这些初步研究的基础上，我们建议使用各种分子和细胞生物学技术来检查自噬在先天和适应性免疫反应中的重要性，并使用已建立的病毒感染小鼠模型。在第一个目的中，我们将通过使用分子和细胞生物学技术来确定ATG5和/或自噬通过TLR9通过TLR9介导的TLR9信号传导的机制。在第二个目标中，我们建议确定自噬如何通过蛋白质组学和生化方法在VSV感染时调节RNA传感器的激活。在最终目标中，我们将询问树突状细胞如何利用自噬在体外和体内在小鼠中选择性缺陷在树突状细胞群体内的自噬。通过对自噬如何协调对病毒感染的先天和适应性免疫产生的基本了解，这些研究将有助于建立重要的基础，以设计疫苗和抗感染测量，以针对多种病毒病原体进行。公共卫生相关性：虽然自噬是一种古老的进化保守途径，旨在通过降解长寿命蛋白和细胞器中的细胞稳态来维持细胞稳态，但我们小组和其他人的最新研究揭示了自噬在免疫系统中的作用。在此应用中，我们建议使用良好的遗传，生化和细胞生物学工具以及RNA和DNA病毒感染的体内动物模型，研究自噬在先天和适应性抗病毒药免疫反应中的重要性。从拟议的研究中获得的理解不仅将在免疫系统使用自噬如何利用自噬方面取得科学进步，而且还可以帮助建立关键基础，以设计免疫学干预措施和预防措施，以防止各种病毒疾病。