Mitochondrial Dysfunction and Aberrant Immune Activation in the Pathobiology of Gulf War Illness
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Background: Gulf War Illness (GWI) is a chronic, multi-symptom disorder affecting approximately 25% to 33% of the nearly 700,000 Veterans of the 1991 Persian Gulf War. The exact etiology of GWI is unknown, but a prevailing hypothesis suggests that environmental exposures experienced by deployed military personnel may underlie disease pathology. Veterans of this conflict encountered a significant number of chemical exposures including chemical warfare agents, prophylactic compounds to protect against warfare agents, significant pesticide usage, and inhaled pollutants from burning oil fields. Consequently, much research has focused on the role of prevalently utilized compounds as causative GWI agents, including reversible acetylcholinesterase inhibitors such as pyridostigmine bromide (PB) and pesticides such as permethrin (PER). Although the mechanisms are unclear, these agents have been suggested to increase oxidative stress and mitochondrial dysfunction, both of which are implicated in a wide array of human diseases, including neurodegeneration, inflammatory disorders, and cancer. Recent studies from our laboratory have demonstrated that mitochondrial dysfunction can activate innate immunity and sterile inflammatory processes. As clinical studies of GWI patients have documented evidence of both mitochondrial dysfunction and immune perturbations, it is possible that mitochondrial dysfunction and/or immune responses triggered by mitochondrial damage may contribute to neurological, musculoskeletal, and other symptoms of GWI. Therefore, more in-depth studies are warranted to clarify mitochondrial and immunological contributions to GWI pathobiology.Objective/Hypothesis: The overall objective for this proposal is to elucidate the etiology of GWI in terms of mitochondrial dysfunction and subsequent immune activation, two important Fiscal Year 2016 Gulf War Illness Research Program Areas of Emphasis. We hypothesize that persistent mitochondrial dysfunction is an important driver of GWI pathobiology, and we propose that mitochondrial dysfunction aberrantly engages the innate immune system to enhance inflammatory and interferon responses, thus exacerbating GWI symptoms. Furthermore, we hypothesize that bezafibrate, a Food and Drug Administration-approved, lipid-lowering drug that boosts healthy mitochondrial function and lowers inflammation, will alleviate neuropathology and cognitive dysfunction in a rodent model of GWI.Aims and Study Design: Specific Aim 1: Determine that mitochondrial dysfunction and aberrant triggering of innate immune responses contribute to the development of GWI pathology. To complete this work, we will utilize a well-characterized mouse model of GWI. In Aim 1A, mice will be exposed to PB + PER or vehicle control, and 4 and 12 months post-exposure, we will employ a battery of neurobehavioral tests to characterize mood and cognitive function. We will also use multiple assays to characterize mitochondrial dysfunction and immune activation and define links between neuroinflammation and the onset/persistence of GWI-related neurobehavioral symptoms. In Aim 1B, we will utilize three mutant mouse strains with deficiencies in key immune pathways (NLRP3, TLR9, and STING) to determine if innate immune signaling and downstream inflammatory responses impact GWI development and/or progression in the PB + PER model. Specific Aim 2: Establish that a pharmacological approach to boost mitochondrial function and decrease inflammation improves GWI-related symptoms. In this aim, we will test the hypothesis that daily administration of bezafibrate (0.5% in normal mouse chow) after the onset of GWI-related symptoms improves mitochondrial function, decreases inflammation, and alleviates neuropathology to improve cognitive and mood impairments in this mouse model of GWI.Impact: This research will examine the mechanistic underpinnings of mitochondrial dysfunction in GWI and will expand upon the important concept of the immune system as a driver of GWI pathobiology. If successful, our findings will significantly impact GWI research because the mitochondrial-immune axis will be recognized for the first time as a major contributor to GWI pathobiology. Moreover, we will explore the novel concept that bezafibrate therapy can lessen GWI-related neurobehavioral symptoms by decreasing mitochondrial dysfunction and inflammation. As bezafibrate is a well-tolerated and readily available drug, this research could have an immediate impact on the health of afflicted Veterans. By elucidating GWI etiology and exploring a new therapeutic avenue, this proposal will directly impact future GWI research and the development of new treatments for afflicted Veterans.