We have shown that the neurotropic virus, Theiler's encephalomyelitis virus (TMEV), replicates to a much higher degree and causes more extensive demyelination in the CNS of mice genetically lacking the protein tyrosine phosphatase SHP-1 compared to wild type mice expressing SHP-1. Further, oligodendrocytes isolated from these mice replicate TMEV to higher levels in vitro than oligodendrocytes of normal littermates containing SHP-1. This indicates that SHP-1, which we have shown is expressed in CNS glia including oligodendrocytes, plays a role in resisting replication of TMEV in these cells and may relate to increased demyelination seen in infected SHP-1-deficient mice. SHP-1 has been shown to control mitogen-activated protein kinase (MAPK) activities arising from growth factor or neurotrophic factor receptors. Preliminary data show that SHP-1 controls constitutive Erk1/2 activation in CNS oligodendrocytes. Activation of multiple MAPK pathways has been shown to promote numerous classes of viruses. We propose that a main role for SHP-1 under the control of a virus-inducible promoter in CNS oligodendrocytes is to modulate MAPK pathways during TMEV infections thus effectively limiting virus replication. In the absence of SHP-1, we hypothesize that TMEV fully utilizes MAPK to promote virus replication. As such, SHP-1 may be considered an important antiviral state gene in the CNS. Since induction of SHP-1 is believed to be primarily epithelial cell-specific, we believe that these studies will be particularly relevant to the microglial populations of the CNS including oligodendrocytes and astrocytes, which are epithelial in origin. However, the role of constitutive expression of SHP-1 through the constitutive hematopoietic promoter in resisting TMEV infection will also be analyzed because these cells are also important targets for TMEV in the CNS. Finally, we show that expression of a virus-inducible anti-viral state gene, inducible nitric oxide synthase (iNOS), and its product nitric oxide is profoundly and specifically deficient in oligodendrocytes and astrocytes of SHP-1-deficient mice compared to those of normal littermates indicating a severe defect in this important anti-viral system. To elucidate the role of SHP-1 in TMEV infections in the CNS we propose the following specific aims.
In specific aim 1, we will study the mechanism by which SHP-1 promotes iNOS expression in oligodendrocytes, astrocytes, and microglia with attention on possible tissue-specific differences in regulation of iNOS between these cells that relate to observed differences in virus replication in these populations. Second, we show that SHP-1 specifically inhibits Erk1/2 activation in oligodendrocytes and will study related mechanisms by which SHP-1 controls replication of TMEV especially at the translational level in specific aim 2. Third, we have shown that SHP-1 expression is induced during virus infections. The mechanism for virus-inducible SHP-1 at the level of the epithelial promoter 1 will be studied in specific aim 3. We believe that information gained under these specific aims will elucidate mechanisms whereby SHP-1 controls virus infections in oligodendrocytes and perhaps other cells of the CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041593-05
Application #
7013648
Study Section
Special Emphasis Panel (ZRG1-CNBT (01))
Program Officer
Utz, Ursula
Project Start
2001-04-15
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
5
Fiscal Year
2006
Total Cost
$205,943
Indirect Cost
Name
Upstate Medical University
Department
Neurology
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
Christophi, George P; Caza, Tiffany; Curtiss, Christopher et al. (2014) Gene expression profiles in granuloma tissue reveal novel diagnostic markers in sarcoidosis. Exp Mol Pathol 96:393-9
Christophi, George P; Rong, Rong; Holtzapple, Philip G et al. (2012) Immune markers and differential signaling networks in ulcerative colitis and Crohn's disease. Inflamm Bowel Dis 18:2342-56
Christophi, George P; Christophi, Jennifer A; Gruber, Ross C et al. (2011) Quantitative differences in the immunomodulatory effects of Rebif and Avonex in IFN-ýý 1a treated multiple sclerosis patients. J Neurol Sci 307:41-5
Christophi, George P; Hudson, Chad A; Panos, Michael et al. (2009) Modulation of macrophage infiltration and inflammatory activity by the phosphatase SHP-1 in virus-induced demyelinating disease. J Virol 83:522-39
Christophi, George P; Panos, Michael; Hudson, Chad A et al. (2009) Interferon-beta treatment in multiple sclerosis attenuates inflammatory gene expression through inducible activity of the phosphatase SHP-1. Clin Immunol 133:27-44
Christophi, George P; Massa, Paul T (2009) Central neuroinvasion and demyelination by inflammatory macrophages after peripheral virus infection is controlled by SHP-1. Viral Immunol 22:371-87
Christophi, George P; Panos, Michael; Hudson, Chad A et al. (2009) Macrophages of multiple sclerosis patients display deficient SHP-1 expression and enhanced inflammatory phenotype. Lab Invest 89:742-59
Christophi, George P; Hudson, Chad A; Gruber, Ross C et al. (2008) SHP-1 deficiency and increased inflammatory gene expression in PBMCs of multiple sclerosis patients. Lab Invest 88:243-55
Hudson, Chad A; Christophi, George P; Gruber, Ross C et al. (2008) Induction of IL-33 expression and activity in central nervous system glia. J Leukoc Biol 84:631-43
Christophi, George P; Hudson, Chad A; Gruber, Ross et al. (2008) Promoter-specific induction of the phosphatase SHP-1 by viral infection and cytokines in CNS glia. J Neurochem 105:2511-23

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