Cisneros Lab Projects

Research indicates that environmental factors including encephalitic viral infections and resulting neuroinflammation are implicated in the etiology of Alzheimer’s disease (AD), a progressive degenerative disorder that affects over 5 million Americans. The risk for AD is an interaction between inherited and environmental risk factors that, with age, drives pathology resulting in neurodegeneration and disease onset.

It is appreciated that encephalitic viral infections have profoundly detrimental neurological consequences long after acute infection has resolved. Studies demonstrate repeated viral infections induce amyloid beta (AB) production, misfolding and deposition in the brain (30-33). Increased AB deposits activate CNS-resident glial cells, and peripherally circulating innate immune cells to propel inflammatory mediators. Blood brain barrier (BBB) integrity compromise ensues to provoke infiltration of peripheral inflammatory cells and virus (34- 38). Neuroinflammation and resultant AB deposition provides a rationale for the overarching hypothesis that the neuropathological consequences of these infections are contributing to sporadic AD.

Despite a link between AD, herpes simplex virus (HSV) in the brain, and CNS encephalitis, there is little insight into mechanisms underpinning sporadic AD to brain viral pathogens. Therefore, it is critical to study the impact of virus, host innate immune responses and systemic and CNS inflammatory responses on the pathology of AD. Advances in this research could advance immunological profiling for sporadic AD and reveal preventative and treatment strategies related to CNS and systemic immunity in AD.

The long-term goal is to investigate treatment interventions for sporadic AD and the infectious disease risk factors impacting peripheral/CNS immune responses in the progression of AD. Using the attenuated Venezuelan equine encephalitis virus (VEEV), TC-83, one of the most common neurotropic, mosquito-borne alphaviruses associated with neurological sequelae in the Americas, we will address our overall objective: to delineate AD-like pathology, identify peripheral immune responses, BBB integrity and progression of AD correlative of cognitive decline and host immune response to viral infection. The central hypothesis is that TC-83 is a significant risk for AD via inflammation and will exacerbate AD-like pathology and the prediction that cognitive deficits will be more severe in humanized amyloid precursor protein (APP) mice infected TC-83, during both acute and convalescent phases of encephalitis.

Cocaine reduces CNS immune responses to HIV-1. 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; however, uncontrolled inflammation and the failure to control HIV-1 replication is a continued problem. Pattern recognition receptors (PRRs), such as 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 in triggering inflammatory and antiviral signaling in cocaine and HIV-1.

Cocaine exposure in astrocytes, increases interferons (IFNs) and activity of the IFN stimulated response element (ISRE), presumably via MAVS. We identified that cocaine induces & mitochondrial toxicity, which regulates MAVS function and AIM2 inflammasome activation. We measured increased caspase-1 cleavage with HIV-1 and identify that cocaine exposure in astrocytes is a major regulator of AIM2 priming measured by increased AIM2 levels, an IFN stimulated gene (ISG). 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 NFκB signaling and IFN production. We established that repeated cocaine exposure reduced MAVS cleaved products and increased MAVS aggregation, which differentially dictate IFN and NFκB signaling, and we measured increased cytokines/chemokines and decreased IFNβ. 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. ASC is regulated by kinases initiated by MAVS and IFN signaling 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 decrease antiviral signaling, promoting astrocyte-induced neurotoxicity in cocaine and HIV-1.