A role for autophagy in increased cytosolic viral signaling in aging

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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.