Faculty bio page2

Irma (Lisa) Cisneros, PhDAssistant Professor

Department of Pathology
Center for Addiction Research
Phone: (409) 772-3938
Email: ircisner@utmb.edu

Irma (Lisa) Cisneros, PhD

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-mediated 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 fentanyl 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 antiviral 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 (AIM2)-like receptor inflammasomes, regulate inflammatory and antiviral signaling. Our preliminary data shows that repeated exposure of astrocytes to cocaine (10 mM), increases proinflammatory cytokines and decreases type I interferons (IFNs); contrary to results occurring 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 ubiquitination of adaptor apoptosis-associated specklike protein (ASC). 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.
  4. Behavioral characterization of animal models of disease: We are characterizing the onset and severity of altered animal behavior and Alzheimer’s disease pathology in genetically modified animals following viral infection.More viruses are identified to enter the central nervous system, but we do not know how they may increases susceptibility to neurological disorders.Using TC-83 as our viral model, we will evaluate viral infection of the brain on the development of Alzheimer’s, this will provide us with knowledge on the role of inflammation on Alzheimer’s disease progression. Our studies are aimed at evaluating hippocampus-selective learning and memory performance in mice that represent models of neurodegenerative diseases at different ages. Our aim is to identify neurological infection/disease and associated alterations to behavior following TC-83 inoculation.
BS University of Texas at Brownsville Biology 2007
PhD University of North Texas Health Science Center Cellular Neuroimmune Pharmacology 2015
Postdoc University of Texas Medical Branch Addiction Research and Neuroinfectious Disease 2019
E. Fitzgerald Sporar Endowment Travel award 2019
ECOR Department of Pathology Pilot Funding 2019
Invited participant, American College of Neuropsychopharmacology Conference, 2018
Postdoctoral Poster Award, Pathology Research Day 2018
Invited speaker, “Impact of Substance Abuse on Neuroimmune Function,” SNIP/ISNV 2018
NIDA F32, Postdoctoral Recipient,  University of Texas Medical Branch, Galveston, TX 2018
Invited speaker, University of California San Diego (UCSD) 2018
Postdoctoral Extramural Research Service Award, UTMB 2017
NIH/NINDS BRAINS Fellow & Participant, Bainbridge Island, WA 2017
NIH Future Leaders Conference Fellow & Participant 2016
NIDA T32, Postdoctoral Recipient, University of Texas Medical Branch 2016
NIH/NIDA Diversity Scholars Network Fellow 2016
Translational Research Seminar Speaker, University of Texas Rio Grande Valley (UTRGV) 2016
Key Note Speaker, MBRS-RISE Induction Ceremony, UTRGV 2016
2nd Place poster presentation, Society for Neuroimmune Pharmacology 2015
Travel Award Recipient, Society for Neuroimmune Pharmacology, Miami, FL 2015
Dean’s Award for Achievement in Academic Excellence, UNTHSC 2015
Outstanding Graduate Student in Cell Biology and Immunology, UNTHSC 2014-2015
F31 Fellowship Recipient, NIH/NIDA, 2014-2015
Travel Award Recipient, Society for Neuroimmune Pharmacology 2014
Certificate of Excellence, Society for Neuroimmune Pharmacology, San Juan, PR 2013
Invited Student Member, American Association for the Advancement of Science 2012-2015
Institute for Aging and Alzheimer’s Disease Research (IAADR) Associate Fellow 2011-2012
Initiative to Maximize Student Development – Minority Biomedical Research Support (IMSD-MORE) 2009-2011
Recognition of Outstanding Research in Marine Biology, NOAA and Cea-CREST 2007
First Place poster presentation, University of Texas at Brownsville 2006
Minority Biomedical Research Support – Research Initiative for Scientific Enhancement (MBRS-RISE) Fellowship Award, University of Texas at Brownsville, 2005-2007
Society for Neuroscience 2019-2020
Sigma Xi 2015-2018
Society for the Advancement of Chicanos and Native Americans in Science (SACNAS) 2013-2019
American Society for Microbiologists 2013-2017
National Hispanic Science Network on Drug Abuse 2012-2019
American Association for the Advancement of Science, Student Member 2012-2015
Society for Neuroimmune Pharmacology 2010-2019
Cisneros IE; Erdenizmenli M; Cunningham KA; Paessler S; Dineley KT. Cocaine evokes a profile of oxidative stress and impacts innate antiviral response pathways in astrocytes. Neuropharmacology, Feb 2018. Doi: 10.1016/j.neuropharm.2018.03.019
Dimet, AL*, Cisneros IE*, Fox RG, Stutz SJ, Anastasio NC, Cunningham KA, Dineley KT. Measuring Cue Reactivity in a Cocaine Self-Administration Rat Model, Journal of Visualized Experiments, 2017. Share first authorship.
Cisneros IE, Ghorpade A. Methamphetamine and HIV-1-induced neurotoxicity: Role of trace amine associated receptor 1 cAMP signaling in astrocytes. Neuropharmacology, 2014 Oct;85:499-507. Doi:10.1016/j.neuropharm.2014.06.01 PMID: 24950453.
Fields J, Cisneros IE, Ghorpade A. Extracellular regulated kinase ½ signaling is a critical regulator of interleukin-1B-mediated astrocyte tissue inhibitor of metalloproteinase-1 expression. PLos One.  2013; 8(2):e56891. Published online 2013 February 14.doi:10.1371/journal.pone.0056891 PMCID: PMC3572966.
Cisneros IE, Ghorpade, A. HIV-1, Methamphetamine and Astrocyte Glutamate Regulation: Combined excitotoxic implications for Neuro-AIDS, Current HIV Research. 2012 May 11. PMID: 22591363. PMCID: PMC3580828.