• Irma (Lisa) E. Cisneros, Ph.D.

    CisnerosAssistant Professor
    T32 Participating Faculty Member
    Department: Pathology

    Email: ircisner@utmb.edu
    Phone: 409.772.3938

    Bio & Research


The overarching goal of the Cisneros Lab is to understand the mechanisms dictating interactions between the immune system and nervous system during substance use disorders and neuroinfectious diseases. Increasing evidence demonstrates that the immune system plays a critical role in both normal and pathological processes in the central nervous system. A particular interest is on immunocompetent cells of the CNS, including astrocytes and microglia, and their innate immune responses, both inflammatory and antiviral during substance use disorders and CNS viral infections. Using in vivo, ex vivo, and in vitro models, we focus on neuroimmune interactions in addiction and viral-medicated neurodegeneration.

1. Opioid self-administration, impulsivity and CNS innate immunity: The Centers for Disease Control reported that approximately 60,000 deaths in the United States were attributable to the misuse of illicit and prescription opioids in the 12-month period ending in September 2017. The intertwined misuse of prescription opioids with the emergence of extremely potent fentanyl derivatives has triggered even greater concerns in the nation. In the absence of overdose deaths, the incidence of repeated opioid overdose events indicates a problematic use pattern consistent with the development of the medical condition of opioid use disorder (OUD). Dysregulation of the brains higher order circuits is fundamentally involved in the progressive behavioral changes that promote OUD and relapse, specifically through structural, functional and molecular alterations and adaptations in the prefrontal cortex (PFC) and nucleus accumbens (NAc). Increasing evidence suggest that neuroimmune signaling forms a vital role in the neuropathology and behavioral indicators of OUD. Peripherally derived immune factors may influence increased cytokine expression, reactive gliosis, antigen-presentation markers and NF-kB transcriptional activity within the PFC and NAc, profoundly influencing neuroplasticity that reinforces OUD. Therefore, we are evaluating changes in neuroimmune markers in various brain regions and in the periphery following fentanly self-administration. We hope to uncover the relationship of fentanyl and/or heroin self-administration and immune function because the host immune response is critical to address future translational aspects of vaccine development and the host immune response to viral infection.

2. Cocaine and regulation of astrocyte mitochondrial anitviral signaling (MAVS) protein during CNS viral infection: Cocaine is the second highest used illegal drug in the US, decreasing the users ability to fight off infections and increasing the severity and onset of HIV-1-mediated neuroinvasion and neurotoxicity, mechanisms likely to exacerbate ZIKV-mediated neurotoxicity as well. Astrocytes are the first line of defense against neurotoxicity associated with cocaine abuse and invading pathogens, becoming activated and initiating a robust innate immune response to pathogens. Astrocyte release of proinflammatory cytokines, upon cocaine treatment is well documented, however; the molecular mechanisms and regulation of cocaine on antiviral responses, thereby impacting HIV-1-induced innate immunity, remains elusive. Our preliminary data, in human astrocytes infected with human immunodeficiency virus-1, (HIV-1, retrovirus) and infected with Zika virus (ZIKV, neurotrophic ssRNA virus), demonstrates that cocaine alone does not increase astrocyte inflammatory responses, but robustly increases IFNb alone, suggesting activation of interferon response factor (IRF) signaling. Interestingly, we observed cocaine-mediated regulation of astrocyte oxidative stress, mitochondrial fission/fusion proteins, membrane permeability, IRF3 signaling and neuroinflammatory changes with antioxidants; which are outcomes identified to regulate mitochondrial antiviral signaling (MAVS) protein function, a mitochondrial scaffolding protein that initiates IRF and NF-kB signaling via recruitment of TNF associated factor (TRAF) proteins. Lastly, cocaine reduces cleavage of astrocyte MAVS and increases aggregation of MAVS in normal human astrocytes (NHA), which is reported to result in a preferential activation of IRF signaling and decreased NF-kB signaling. AStrocyte MAVS regulation by cocaine is highly significant, in that it may dictate the balance of viral-induced activation of astrocyte innate immune responses having larger implications in innate immune responses to CNS viral infections during cocaine use.

3. HIV-1 and cocaine astrocyte-induced innate immunity: AIM(2)ing at the inflammasome: Astrocytes are the first line of defense during cocaine abuse and HIV-1, initiating a robust innate immune response. Mitochondrial antiviral signaling protein (MAVS), together with absent in melanoma 2 (AIMS2)-like receptor inflammasomes, regulate inflammatory and anitviral signaling. Our preliminary data shows that repeated exposure of astrocytes to cocaine (10mM), increases proinflammatory cytokines and decreases type I interferons (IFNs); contrary to results occuring subsequent to transient cocaine exposure, which does not influence proinflammatory cytokines and increases type I IFNs. Moreover, transient cocaine exposure triggers dose-dependent increases of reactive oxygen species (ROS), [Ca+2]i and mitochondrial damage, outcomes reported to regulate MAVS activation. Repeated cocaine exposure or HIV-1 treatments alone or with cocaine, increase dsDNA; a product that initiate MAVS and AIM2 signaling. The relationship between MAVS and AIM2 is not identified; however, MAVS promotes inflammasome activation via TNF associated factor (TRAF)3 ubiqitination of adaptor apoptosis-associated specklike protein (ACS). Furthermore, ASC inhibits MAVS ability to induce antiviral signaling through CARD-CARD homotypic interactions. MAVS-induced antiviral signaling is regulated by cleavage and aggregation, dictating downstream interactions and differentially activating NFkB and IFN response factor (IRF) signaling. Repeated cocaine exposure decreases MAVS signaling and increases MAVS aggregation, suggesting cocaine impacts MAVS functional capacity. AIM2 positively correlates with IFNb levels induced by cocaine, suggesting cocaine-induced IFNb, regulates AIM2 transcription, which is an IFN stimulated gene. Lastly, astrocytes transfected with siMAVS, reduced IFNb and AIM2 levels following cocaine exposure, compared to Mock and siCON-transfected astrocytes treated with cocaine. We hope to uncover the interactions between MAVS and AIM2 signaling in regulating innate immune responses during substance use disorders and HIV-1 CNS infection.

  • B.S., 2007, University of Texas at Brownsville
  • Ph.D., 2015 University of North Texas Health Science Center