Microglia and other brain macrophages are the principal regulators of neuroinflammation within the CNS. Herpes simplex virus (HSV)-1 is an important opportunistic pathogen in HIV-1-infected patients as well as the cause of a devastating CNS infection in normal hosts. It is well established that the brain damage seen during neuroAIDS is not caused by direct HIV infection of neurons, but rather is induced by macrophage-produced neuroinflammatory mediators. Microglial cells produce these same neuroinflammatory mediators in response to HSV, and this proposal utilizes HSV infection of mice as a small animal model to investigate the role of activated microglia during viral brain infection. The central hypothesis to be tested is that oxidative stress occurring during viral encephalitis can be modulated to prevent immune-mediated mechanisms of tissue damage. To test this hypothesis, we will (1) determine whether TLR2 mediates oxidative stress occurring during herpes encephalitis. This will be achieved by comparing virus-induced production of pro-oxidative enzymes and reactive species using cultured microglia isolated from wild-type versus TLR2 knockout mice. Additional experiments will compare oxidative stress-induced brain damage occurring during viral encephalitis following infection of these knockout animals. We will then (2) determine whether antioxidant enzymes regulate oxidative stress during viral encephalitis. These studies will examine the effect of select antioxidant enzymes on the production of reactive species and microglial cell apoptosis in response to HSV. We will go on to examine the role of these antioxidant enzymes in controlling oxidative stress-induced brain damage during viral encephalitis in vivo. Finally, we will (3) determine if virus-induced oxidative brain damage can be controlled. This will be achieved through overexpressing anti-inflammatory cytokines in the brains of iNOS-luciferase transgenic mice and assessing expression using in vivo real-time bioluminescence imaging. In the final studies, we will modulate the oxidative stress response occurring during herpes encephalitis. This will be achieved by constructing recombinant herpesviruses overexpressing vaccinia virus proteins that disrupt TLR signaling, as well as antioxidant enzymes, and assessing the resulting tissue damage in infected animals. Through studies described in this proposal, we hope to identify new approaches for treatment of herpes encephalitis and neuroAIDS, as well as other forms of viral encephalitis, which reduce the extent of immune-mediated brain damage.
It is well established that brain damage seen during neuroAIDS is not caused by direct HIV infection of neurons, but rather is induced by microglial cell- produced neuroinflammatory mediators, such as reactive oxygen and reactive nitrogen species. Through the use of inhibitors of microglial cell activation and antioxidant enzymes, it may be possible to modulate the oxidative stress response occurring during viral encephalitis. In these experiments, we hope to identify new approaches to the treatment of herpes encephalitis and neuroAIDS, as well as other forms of viral encephalitis, which reduce the extent of immune- mediated mechanisms of brain damage.
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|Schachtele, Scott J; Hu, Shuxian; Sheng, Wen S et al. (2014) Glial cells suppress postencephalitic CD8+ T lymphocytes through PD-L1. Glia 62:1582-94|
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|Marques, Cristina P; Cheeran, Maxim C-J; Palmquist, Joseph M et al. (2008) Microglia are the major cellular source of inducible nitric oxide synthase during experimental herpes encephalitis. J Neurovirol 14:229-38|
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