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。对病毒感染的先天免疫是通过模式识别受体（PRRs）对独特病毒特征的识别而启动的，模式识别受体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。最近有研究表明，受感染细胞内的病毒识别是由细胞质中视黄酸诱导基因I样受体（RLR）家族成员介导的，但迄今为止还没有研究RLR信号传导是否受年龄影响的报道。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增加：(1)在没有自噬的情况下，(2)在氧化应激增加的情况下，(3)在老年人中。这些数据提示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运送到溶酶体降解来维持它们的完整性。我已经证明，自噬的缺失会通过两种方式导致RLR信号的放大（以及细胞因子的产生增加）。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，受损的线粒体不被降解，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。有趣的是，我对老年志愿者的原代细胞的研究反映了这种模式。老年人巨噬细胞的线粒体ROS和RLR信号水平明显高于年轻人。据推测，衰老过程中氧化应激水平的增加是许多衰老和迟发性疾病病理的潜在原因，从动物模型中可以推断，氧化应激水平的增加是自噬功能随着年龄的增长而下降的结果。我的目标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增加了RLR信号，并发现两者在老年巨噬细胞中都显著升高，我的目标是研究氧化应激对细胞内抗病毒信号随年龄增长的影响，以了解老年人中增加的炎症特征，以及这对流感的促炎反应的影响。这项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对病毒感染的先天免疫反应的功能影响。