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

Department of Ophthalmology, University of Chicago, Chicago, IL, USA.
Journal of Neuroinflammation (Impact Factor: 5.41). 11/2008; 5(1):48. DOI: 10.1186/1742-2094-5-48
Source: PubMed


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 alphaPD1 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.

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    • "In marked contrast to the periphery, the brain content of KYNA, 3- HK and QUIN was dramatically increased 4 weeks after infection with T. gondii, i.e. at a time when the parasite is largely controlled in the periphery (Vyas et al., 2007). This chronic phase is characterized by the presence of numerous cysts and inflammation in the brain, with activation of astrocytes and microglia (Hermes et al., 2008; Wilson and Hunter, 2004), as confirmed here by histological means. As these glial cells produce IDO and the other enzymes that are responsible for the cerebral biosynthesis of neuroactive kynurenines, and as the formation of these metabolites in the brain is known to be enhanced after immune stimulation (see Schwarcz et al., 2012 for review), it is likely that synthesis within the brain accounted for the observed changes in brain KP metabolism at this stage after infection. "
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    Schizophrenia Research 12/2013; 152(1). DOI:10.1016/j.schres.2013.11.011 · 3.92 Impact Factor
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    • "These can be detected easily as hyperintensities in T 2 weighted images [14] [15]. Thus, lesions in the brain with bright MRI signals have been detected and characterized successfully with respect to Shiga toxin-producing Escherichia coli infections [16], Herpes simplex encephalitis (Fig. 2) [17] [18] [19], Cryptococcal meningoencephalitis [20], Citrobacter koseri brain abscesses [21], sepsis-associated encephalopathy [22], Lymphocytic Choriomeningitis Virus infections [23], and Toxoplasma gondii brain infections [24]. Recently, endogenous T 2 contrast was also defined as early marker of cerebral malaria, one of the most severe complications caused by Plasmodium falciparum. "
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    • "For example, T. gondii persists in human pseudocysts, macrophages, and neurons. In the latent phase the parasite is in the bradyzoite stage and causes mild inflammation as a result of the host’s immune response [63]. However, dying cysts probably cause intense inflammation. "
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