Microglial GLT‐1 is upregulated in response to herpes simplex virus infection to provide an antiviral defence via glutathione

Abstract

Herpes simplex virus (HSV) can enter the central nervous system and cause encephalitis (HSV-1) or meningitis (HSV-2). Microglia, the immunocompetent cells of the central nervous system, are potentially able to detect viral infections. Microglia have been shown to express the glutamate transporter GLT-1 during pathological events, leading to increased microglial glutamate uptake and glutathione synthesis. This study aims to address the role of GLT-1 and glutathione, a major antioxidant with antiviral properties, during HSV infections. Using neuron-enriched mixed primary cultures from rat, it was found that microglia have higher resistance to HSV infections than neurons or astrocytes after 24 h incubation with HSV. Purified microglia in culture were used to further address this. It was found that microglia were able to detect HSV and responded by releasing tumor necrosis factor-alpha (TNF-alpha) and upregulating GLT-1 after 24 h incubation with 1 PFU/cell HSV-1 or HSV-2. Furthermore, the microglial glutathione levels were not significantly diminished after 24 h. Inhibition of the microglial glutathione synthesis with 200 microM buthionine sulfoximide (BSO) led to significantly more infected cells after 24 h incubation with 1 PFU/cell HSV-1 or HSV-2. These data indicate that the higher resistance in microglia against HSV infections may be due to the expression of GLT-1, which can maintain the glutathione levels and provide a mechanism for microglial self-defense against HSV.

Lactate Contributes to Ammonia-Mediated Astroglial Dysfunction During Hyperammonemia

“…Interestingly, glutamate uptake capacity in GLT-1-expressing microglial cultures, was not significantly affected by neither lactate nor NH 4 Cl, suggesting that astroglial cells are more vulnerable to hyperammonemia. This finding might be directly connected to differences in astroglial and microglial GLT-1 expression and regulation, which previously have been reported from this laboratory [13,25,26].…”

Physiology of Microglia

“…The GLT-1 transporter is upregulated in microglial cells exposed to the Herpes simplex virus of both HSV-1 (encephalitis) and HSV-2 (meningitis) types (708). Microglial cells also demonstrated a higher resistance to HSV viruses compared with neurons and astrocytes (708).…”

“…The GLT-1 transporter is upregulated in microglial cells exposed to the Herpes simplex virus of both HSV-1 (encephalitis) and HSV-2 (meningitis) types (708). Microglial cells also demonstrated a higher resistance to HSV viruses compared with neurons and astrocytes (708). This higher resistance can result from upregulated GLT-1 transporters, which in turn are instrumental in increasing microglial glutathione content, as the microglial glutamate uptake was shown to be directly coupled to glutathione synthesis (710).…”

Glutamine antagonist-mediated immune suppression decreases pathology but delays virus clearance in mice during nonfatal alphavirus encephalomyelitis

“…GLT1/EAAT2, which is primarily expressed by astrocytes but also found on microglia, is responsible for the majority of glutamate uptake from the synaptic cleft and thus an important player in the prevention of excitotoxicity (Danbolt, 2001). Several CNS virus infections, including NSV, human coronavirus (HCoV)-OC43, human T-lymphotropic virus, and human cytomegalovirus, downregulate GLT1 expression (Akaoka et al, 2001; Brison et al, 2011; Darman et al, 2004; Prow and Irani, 2008; 2007; Zhang et al, 2014), but others, including herpes simplex virus and Japanese encephalitis virus infection, induce upregulation (Mishra et al, 2007; 2008; Persson et al, 2007). In our study, SINV infection reduced GLT1 expression in the brain as determined by both IHC and immunoblot at 7 DPI compared to mock-infected control mice.…”