Despite advances in immunization, viral infections of the central nervous system (CNS) remain a devastating cause of encephalitis and neurodegeneration, particularly in the young, elderly, and immunocompromised. Neurons are principally non-renewable and traditional mechanisms of viral clearance that are employed in the periphery, such as cytolysis of infected cells, could prove detrimental if targeted towards CNS neurons. While it is clear that the immune system can limit viral spread in the brain, the mechanisms by which infected neurons respond to the inflammatory environment created by immune infiltration into the brain remain largely undefined. This is especially important given the potential role of inflammation in diseases of unknown etiology, such as multiple sclerosis, amyotropic lateral sclerosis, Parkinson's and Alzheimer's disease. This proposal will determine how unique interferon-induced signaling in neurons may help these cells control and ultimately survive viral infection. A transgenic mouse has been created that expresses higher levels of STAT1 selectively in neurons. STAT-1 and STAT2- deficient mice will be utilized as well. These models will be used to determine whether altered STAT expression has an effect on neuronal responsiveness to interferons, as well as whether this may have an effect on viral replication, spread, and clearance in the CNS. Studying how neurons respond to essential cytokines such as interferons can potentially lead us to a greater understanding of not only how virus is cleared from the CNS without sacrificing neuronal viability, but also how neurons themselves play a role in this process.
Diseases such as multiple sclerosis, amyotropic lateral sclerosis, Parkinson's and Alzheimer's disease are thought to involve an infectious and/or inflammatory component. By further discerning how neurons interact with the immune system, we may gain a greater understanding of how diseases of the central nervous system (CNS) develop. The proposed project will yield clinically relevant data that could lead to improved or novel therapeutic strategies for the treatment of multiple sclerosis, injury due to stroke, and other diseases of the CNS.
|Holmgren, Alicia M; Miller, Katelyn D; Cavanaugh, Sarah E et al. (2015) Bst2/Tetherin Is Induced in Neurons by Type I Interferon and Viral Infection but Is Dispensable for Protection against Neurotropic Viral Challenge. J Virol 89:11011-8|
|Cavanaugh, Sarah E; Holmgren, Alicia M; Rall, Glenn F (2015) Homeostatic interferon expression in neurons is sufficient for early control of viral infection. J Neuroimmunol 279:11-9|