A role for autophagy in increased cytosolic viral signaling in aging

自噬在衰老过程中细胞质病毒信号传导增强中的作用

• 批准号: 8197961
• 负责人: Michal Caspi Tal
• 金额: $ 2.66万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-17 至 2012-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197961
• 关键词: Affect; Age; Aging; Aging-Related Process; Animal Model; Antiviral Agents; Autophagocytosis; Biological; Cell physiology; Cells; Cessation of life; Cytosol; Data; Defect; Elderly; Family; Genes; Goals; Hospitalization; Human; Immune response; Infection; Inflammatory; Inflammatory Response; Influenza; Interferon Type I; Knock-out; Lead; Life; Ligands; Link; Lung Inflammation; Lung diseases; Lysosomes; Mediating; Mediator of activation protein; Mitochondria; Modeling; Molecular; Natural Immunity; Organelles; Oxidative Stress; Pathogenesis; Pathology; Pattern; Pattern recognition receptor; Predisposition; Process; Production; Proteins; Reactive Oxygen Species; Regulation; Reporting; Role; Severity of illness; Signal Transduction; Signaling Protein; Source; Tretinoin; Ursidae Family; Viral; Virus Diseases; age effect; age related; burden of illness; cytokine; functional decline; immune function; immunosenescence; induced pluripotent stem cell; late disease onset; macrophage; member; pathogen; prevent; protein transport; public health relevance; receptor; response; theories; therapy development; volunteer; young adult

DESCRIPTION (provided by applicant): While the age-dependent decline in the immune response to a variety of pathogens is accompanied by an increase in circulating levels of proinflammatory mediators, the reason for this association remains unclear. Innate immunity to viral infection is initiated through the recognition of unique viral signatures by pattern recognition receptors (PRRs) that mediate the induction of potent antiviral factors, type I interferon's (IFNs) and other pro-inflammatory cytokines. It has recently been elucidated that viral recognition within an infected cell is mediated by members of the retinoic acid inducible gene I -like receptor (RLR) family in the cytosol, yet no report to date has examined if RLR signaling is affected by age. Here, I show that pro-inflammatory cytokine production in response to viral ligands is increased in several situations: (1) in the absence of autophagy, (2) during increased oxidative stress, and (3) in the elderly. These data suggest a possible mechanism for the increased cytokine production and impaired immune function observed in the elderly which I propose to investigate. The process of autophagy maintains the integrity of cellular organelles and long-lived proteins by transporting them to the lysosomes for degradation. I have shown that the absence of autophagy leads to the amplification of RLR signaling (and increased cytokine production) in two ways. First, in the absence of autophagy, mitochondria accumulate within the cell along with the mitochondrial associated protein, IPS-1, a key signaling protein for RLRs. Second, damaged mitochondria that are not degraded in the absence of autophagy provide a source of reactive oxygen species (ROS), which amplified RLR signaling in Atg5 knockout cells. Interestingly, my studies on primary cells from elderly volunteers mirrored this pattern. Macrophages from elderly showed significantly higher levels of mitochondrial ROS and RLR signaling than macrophages from young adults. It has been postulated that the increased levels of oxidative stress seen in aging are the underlying cause for many of the pathologies seen in aging and in late onset diseases, and it has been inferred from animal models that this increased oxidative stress results from the decline of function of autophagy with age. I aim to characterize autophagic flux in healthy human aging by examining the extent to which autophagy is decreased or dysfunctional and the impact this bears on the accumulation of damaged mitochondria and the resultant increase in levels of ROS. As I have reported that ROS increases RLR signaling, and have found both to be strikingly elevated in elderly macrophages, I aim to examine the impact of oxidative stress on cytosolic antiviral signaling with age in order to understand the increased inflammatory profile seen in the elderly, and the effect that this has on the pro-inflammatory response to influenza. The study outlined in this proposal will examine the crossroads between important cellular processes fundamental in both the aging process and antiviral defense, with the goal of uncovering the functional implications for the accumulation of damaged mitochondria and oxidative stress on the innate immune response to viral infection in the elderly. PUBLIC HEALTH RELEVANCE: It is physically apparent to everyone observing from the outside that we are constantly aging, yet, the biological mechanisms responsible for this are still unclear. I am proposing to investigate to what extent the cellular clean-up crew, autophagy, lags with age, resulting in the accumulation of damaged components within our cells. I will then examine how this impacts the pathologies seen in aging, specifically the way in which a cell recognizes and responds to viral infection with age.

描述（由申请人提供）：虽然对多种病原体的免疫反应随年龄而下降，并伴随着促炎介质循环水平的增加，但这种关联的原因仍不清楚。针对病毒感染的先天免疫是通过模式识别受体 (PRR) 识别独特的病毒特征来启动的，模式识别受体 (PRR) 介导强效抗病毒因子、I 型干扰素 (IFN) 和其他促炎细胞因子的诱导。最近已阐明，受感染细胞内的病毒识别是由细胞质中的视黄酸诱导基因 I 样受体 (RLR) 家族成员介导的，但迄今为止尚未有报告检查 RLR 信号传导是否受年龄影响。在这里，我表明，在几种情况下，响应病毒配体的促炎细胞因子的产生会增加：（1）在没有自噬的情况下，（2）在氧化应激增加期间，以及（3）在老年人中。这些数据表明了在老年人中观察到的细胞因子产生增加和免疫功能受损的可能机制，我建议对此进行研究。自噬过程通过将细胞器和长寿命蛋白质转运至溶酶体进行降解来维持细胞器和长寿命蛋白质的完整性。我已经证明，自噬的缺失会通过两种方式导致 RLR 信号放大（并增加细胞因子的产生）。首先，在没有自噬的情况下，线粒体与线粒体相关蛋白 IPS-1（RLR 的关键信号蛋白）一起在细胞内积累。其次，在没有自噬的情况下不会降解的受损线粒体提供了活性氧 (ROS) 的来源，从而放大了 Atg5 敲除细胞中的 RLR 信号传导。有趣的是，我对老年志愿者原代细胞的研究反映了这种模式。与年轻人的巨噬细胞相比，老年人的巨噬细胞显示出明显更高水平的线粒体 ROS 和 RLR 信号传导。据推测，衰老过程中氧化应激水平的增加是衰老和迟发性疾病中许多病理现象的根本原因，并且从动物模型中推断，氧化应激水平的增加是由于氧化应激水平下降所致。自噬功能随年龄的增长。我的目的是通过检查自噬减少或功能失调的程度以及这对受损线粒体积累和由此产生的 ROS 水平增加的影响来表征健康人类衰老过程中的自噬通量。正如我所报道的，ROS 会增加 RLR 信号传导，并且发现这两种信号在老年巨噬细胞中显着升高，我的目的是检查氧化应激对细胞质抗病毒信号传导随年龄的影响，以了解老年人中炎症的增加，以及这对流感促炎症反应的影响。该提案中概述的研究将检查衰老过程和抗病毒防御中至关重要的重要细胞过程之间的交叉点，目的是揭示受损线粒体积累和氧化应激对病毒感染先天免疫反应的功能影响。老年人。 公共健康相关性：从外表上看，每个人都明显地看到我们在不断衰老，但造成这一现象的生物学机制仍不清楚。我提议调查细胞清理工作、自噬在多大程度上随着年龄的增长而滞后，导致细胞内受损成分的积累。然后我将研究这如何影响衰老过程中的病理学，特别是细胞随着年龄的增长识别和响应病毒感染的方式。