Abstract
BackgroundWorldwide, approximately two billion people are chronically infected with Toxoplasma gondii with largely unknown consequences.MethodsTo 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.ResultsTwelve 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.ConclusionIn 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.
Highlights
Worldwide, approximately two billion people are chronically infected with Toxoplasma gondii with largely unknown consequences
Descriptions of mice and T. gondii infection of mice for behavioral and neurologic assessments, Magnetic Resonance Imaging (MRI), microarrays, and histopathology Swiss Webster mice Female Swiss Webster (SW) mice were bred in our (RM) laboratory and were derived from breeding pairs originally obtained from Harlan Laboratories (Indianapolis, IN)
These results were observed in carefully monitored and characterized Specific Pathogen Free (SPF) mice chronically infected with T. gondii
Summary
Approximately two billion people are chronically infected with Toxoplasma gondii with largely unknown consequences. Understanding the effects of chronic T. gondii infection is important because this parasite chronically infects 30–50% of the human population worldwide [1]. There are a variety of reports that suggest that chronic Toxoplasma infection may alter human behaviors, cognitive functions, and cause cryptogenic epilepsy, headaches, and onset of schizophrenia [e.g., [2,3,4]]. In these studies, investigators have noted increased seroprevalence for past T. gondii infection or increased magnitude of antibody titers specific for T. gondii in sera of persons with these medical problems [5]. None definitively prove a cause and effect relationship [6]
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