R01DA052263

AIM(2)ing at the Inflammasome: Impact of MAVS Signaling in Cocaine- and HIV-1 Induced Neuroinflammation - Project Summary/Abstract

Cocaine, the second highest used illegal drug in the US, reduces CNS immune responses to HIV-1, increasing the severity and onset of HIV-1-mediated neurotoxicity. Astrocytes are the first line of defense against toxicity in the CNS and initiate inflammatory responses to HIV-1 and antiviral activity following cocaine exposure (33). However, uncontrolled inflammation and the failure to control HIV-1 replication is a continued problem.

Mitochondrial antiviral signaling protein (MAVS), together with absent in melanoma 2 (AIM2)-like receptor inflammasomes, their interactions, crosstalk, and dual scaffolding could be key mechanisms triggering inflammatory and antiviral signaling in cocaine and HIV-1. Cocaine exposure in astrocytes increases interferons (IFNs) (33) and activity of the IFN stimulated response element (ISRE), presumably via MAVS. We identified that cocaine induced mitochondrial toxicity, which regulates MAVS function and AIM2 inflammasome activation (30, 77). We discovered that cocaine exposure in astrocytes is a major regulator of AIM2 priming measured by increased caspase-1 cleavage and AIM2 levels, an IFN stimulated gene (ISG) (32, 88). Furthermore, MAVS plays a crucial role in cocaine-induced AIM2 priming as demonstrated in MAVS downregulated astrocytes. Dual overactivation of MAVS and AIM2 produce chronic inflammatory pathologies, via NFB signaling and IFN production (16, 23). We established that repeated cocaine exposure reduced MAVS cleaved products and increased MAVS aggregation, which differentially dictate IFN and NFB signaling, and we measured increased cytokines/chemokines and decreased IFNs. Interestingly, AIM2 binding partner, adaptor associated speck-like protein (ASC), binds MAVS via caspase recruitment domain (CARD)-CARD homotypic interactions to inhibit MAVS-induced IFN generation (35). ASC is regulated by kinases initiated by MAVS and IFN signaling (36, 37) and may play a vital role in promoting AIM2-induced aberrant neuroinflammation and reduced MAVS antiviral signaling, in cocaine and HIV-1.

We hypothesize that cocaine promotes MAVS activation via mitochondrial toxicity, priming AIM2 inflammasomes. Repeated cocaine exposure, and/or HIV-1, results in dual recruitment of ASC to astrocyte MAVS/AIM2. ASC recruitment initiates signal transduction events triggering astrocyte-induced inflammation and decreased antiviral signaling, promoting astrocyte-induced neurotoxicity in cocaine and HIV-1. To test this hypothesis, we will uncover mechanisms by which cocaine causes AIM2 inflammasome priming via astrocyte MAVS activation (Aim 1); delineate astrocyte MAVS and AIM2 scaffolding and crosstalk on AIM2 inflammasome oligomerization and signaling (Aim 2); and explore the impact of astrocyte ASC regulation/recruitment in AIM2 signaling and attenuated MAVS activation in cocaine and HIV-1. Repeated cocaine exposure, and/or subsequent introduction of HIV-1, inundates the innate immune response producing a hyperimmune and decreased antiviral phenotype, increasing the risk of HIV-1 neurotoxicity.

University Of Texas Medical Branch At Galveston

TO SUPPORT BASIC AND CLINICAL NEUROSCIENCE, BIOMEDICAL, BEHAVIORAL AND SOCIAL SCIENCE, EPIDEMIOLOGIC, HEALTH SERVICES AND HEALTH DISPARITY RESEARCH. TO DEVELOP NEW KNOWLEDGE AND APPROACHES RELATED TO THE PREVENTION, DIAGNOSIS, TREATMENT, ETIOLOGY, AND CONSEQUENCES OF DRUG ABUSE AND ADDICTION, INCLUDING HIV/AIDS. TO SUPPORT RESEARCH TRAINING AND RESEARCH SCIENTIST DEVELOPMENT. TO SUPPORT DISSEMINATION OF RESEARCH FINDINGS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) LEGISLATION IS INTENDED TO EXPAND AND IMPROVE THE SBIR PROGRAMS TO EMPHASIZE AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF TECHNOLOGY DEVELOPED THROUGH FEDERAL SBIR RESEARCH AND DEVELOPMENT, INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN THE SBIR PROGRAM. THE LEGISLATION INTENDS THAT THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.279 - Drug Abuse and Addiction Research Programs

National Institute on Drug Abuse (NIDA) [HHS - NIH]

Galveston, Texas 775555302 United States

Single Zip Code

Targeting Inflammasomes in Substance Abuse and HIV (R01 Clinical Trial Not Allowed) (RFA-DA-20-026)

Amendment Since initial award the total obligations have increased 391% from $611,217 to $3,004,104.