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）：虽然对各种病原体的免疫应答的年龄依赖性下降伴随着促炎介质循环水平的增加，但这种关联的原因尚不清楚。通过模式识别受体（PRR）识别独特的病毒特征来启动对病毒感染的先天免疫，所述模式识别受体介导有效的抗病毒因子、I型干扰素（IFN）和其他促炎细胞因子的诱导。最近已经阐明，受感染细胞内的病毒识别是由胞质溶胶中的视黄酸诱导基因I样受体（RLR）家族的成员介导的，但迄今为止还没有报道研究RLR信号传导是否受年龄的影响。在这里，我表明，响应于病毒配体的促炎细胞因子的产生在几种情况下增加：（1）在没有自噬的情况下，（2）在氧化应激增加的过程中，（3）在老年人中。这些数据表明，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，我建议进行调查。自噬过程通过将细胞器和长寿命蛋白质运输到溶酶体进行降解来维持细胞器和长寿命蛋白质的完整性。我已经表明，自噬的缺乏导致RLR信号的放大（和增加细胞因子的产生）在两个方面。首先，在没有自噬的情况下，线粒体在细胞内沿着线粒体相关蛋白IPS-1（RLR的关键信号蛋白）积聚。其次，在没有自噬的情况下不降解的受损线粒体提供了活性氧（ROS）的来源，其在Atg 5敲除细胞中放大了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。老年人的巨噬细胞比年轻人的巨噬细胞显示出显着更高水平的线粒体活性氧和RLR信号传导。据推测，在衰老中观察到的氧化应激水平的增加是在衰老和迟发性疾病中观察到的许多病理的根本原因，并且从动物模型中推断，这种增加的氧化应激是由于自噬功能随年龄的下降。我的目标是通过检查自噬减少或功能障碍的程度以及这对受损线粒体积累的影响以及由此产生的ROS水平增加来表征健康人类衰老中的自噬通量。正如我所报道的那样，ROS增加了RLR信号传导，并且发现两者在老年巨噬细胞中显著升高，我的目标是检查氧化应激对细胞溶质抗病毒信号传导的影响，以了解老年人中观察到的炎症特征增加，以及这对流感促炎反应的影响。该提案中概述的研究将研究衰老过程和抗病毒防御中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老年人先天免疫应答的功能影响。 公共卫生关系：从外表上看，每个人都很明显地看到我们在不断衰老，然而，对此负责的生物机制仍然不清楚。我建议调查细胞清理人员，自噬，随着年龄的增长而滞后的程度，导致我们细胞内受损成分的积累。然后，我将研究这是如何影响衰老过程中的病理变化的，特别是细胞识别和响应病毒感染的方式。