Strathprints Home | Open Access | Browse | Search | User area | Copyright | Help | Library Home | SUPrimo

Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neuronal injury in brains of mice due to common, persistent, parasitic infection

Hermes, Gretchen and Ajioka, James W. and Kelly, Krystyna and Mui, Ernest and Roberts, Fiona and Kasza, Kirsten and Mayr, Thomas and Kirisits, Michael J. and Wollmann, Robert and Ferguson, David J.P. and Roberts, C.W. and Hwang, Jong-Hee and Trendler, Toria and Kennan, Richard P. and Suzuki, Yasuhiro and Reardon, Catherine and Hickey, William F. and Chen, Lieping and McLeod, Rima (2008) Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neuronal injury in brains of mice due to common, persistent, parasitic infection. Journal of Neuroinflammation, 5 (Octobe). ISSN 1742-2094

[img]
Preview
PDF (strathprints013173.pdf) - Published Version
Download (15Mb) | Preview

    Abstract

    Worldwide, approximately two billion people are chronically infected with Toxoplasma gondii with largely unknown consequences. To better understand long-term effects and pathogenesis of this common, persistent brain infection, mice were infected at a time in human years equivalent to early to mid adulthood and studied 5-12 months later. Appearance, behavior, neurologic function and brain MRIs were studied. Additional analyses of pathogenesis included: correlation of brain weight and neurologic findings; histopathology focusing on brain regions; full genome microarrays; immunohistochemistry characterizing inflammatory cells; determination of presence of tachyzoites and bradyzoites; electron microscopy; and study of markers of inflammation in serum. Histopathology in genetically resistant mice and cytokine and NRAMP knockout mice, effects of inoculation of isolated parasites, and treatment with sulfadiazine or αPD1 ligand were studied. Twelve months after infection, a time equivalent to middle to early elderly ages, mice had behavioral and neurological deficits, and brain MRIs showed mild to moderate ventricular dilatation. Lower brain weight correlated with greater magnitude of neurologic abnormalities and inflammation. Full genome microarrays of brains reflected inflammation causing neuronal damage (Gfap), effects on host cell protein processing (ubiquitin ligase), synapse remodeling (Complement 1q), and also increased expression of PD-1L (a ligand that allows persistent LCMV brain infection) and CD 36 (a fatty acid translocase and oxidized LDL receptor that mediates innate immune response to beta amyloid which is associated with pro-inflammation in Alzheimer's disease). Immunostaining detected no inflammation around intra-neuronal cysts, practically no free tachyzoites, and only rare bradyzoites. Nonetheless, there were perivascular, leptomeningeal inflammatory cells, particularly contiguous to the aqueduct of Sylvius and hippocampus, CD4+ and CD8+ T cells, and activated microglia in perivascular areas and brain parenchyma. Genetically resistant, chronically infected mice had substantially less inflammation. In outbred mice, chronic, adult acquired T. gondii infection causes neurologic and behavioral abnormalities secondary to inflammation and loss of brain parenchyma. Perivascular inflammation is prominent particularly contiguous to the aqueduct of Sylvius and hippocampus. Even resistant mice have perivascular inflammation. This mouse model of chronic T. gondii infection raises questions of whether persistence of this parasite in brain can cause inflammation or neurodegeneration in genetically susceptible hosts.

    Item type: Article
    ID code: 13173
    Keywords: neurological abnormalities, behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, neuronal injury, brains, mice, parasitic infection, pharmacology, Therapeutics. Pharmacology, Pharmacy and materia medica, Microbiology, Cellular and Molecular Neuroscience, Immunology, Neurology
    Subjects: Medicine > Therapeutics. Pharmacology
    Medicine > Pharmacy and materia medica
    Science > Microbiology
    Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Faculty of Science > Mathematics and Statistics
    Related URLs:
      Depositing user: Ms Ann Barker-Myles
      Date Deposited: 07 Oct 2009 13:21
      Last modified: 04 Apr 2014 23:57
      URI: http://strathprints.strath.ac.uk/id/eprint/13173

      Actions (login required)

      View Item

      Fulltext Downloads: