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

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.

Seroprevalence of Toxoplasma gondii Infection in Patients with Alzheimer’s Disease

“…Behavioral changes attributed to infection due to T. gondii may be due to the parasite itself, which causes infection with nerve damage. IFN-γ, the main responsible cytokine for immunological defense against T. gondii is essential in all infected tissues, including the central nervous system (13)(14)(15)(16)(17). The biosynthesis of dopamine and/or serotonin could be directly affected by aromatic amino acid hydroxylases in T. gondii genome.…”

“…The biosynthesis of dopamine and/or serotonin could be directly affected by aromatic amino acid hydroxylases in T. gondii genome. Increase of dopamine in the brains of infected patients can be associated with the missing link between toxoplasmosis and mental disorders (15,18). Although, latent cases treated as asymptomatic and clinically unimportant by medical professionals, results of animal studies and recent studies of personality profiles, behavior, and psychomotor performance have led to reconsider T. gondii infection as a risk factor for the development of some neuropsychiatric disorders, including schizophrenia, parkinson disease (PD) and alzheimer's disease (AD) (10,13,18,19).…”

Effects of Toxoplasma gondii infection on anxiety, depression and ghrelin level in male rats

“…Recent studies demonstrated that T. gondii can modify brain function and intermediate host's behavior (Hermes et al 2008;Vyas et al 2007;Kannan et al 2010), and also increase the chances of serious psychological disturbances such as schizophrenia and bipolar disorders in human (Pearce et al 2012;Mortensen et al 2007). In addition there is correlation between T. gondii infection and mood disorders.…”

Ly6Chigh Monocytes Control Cerebral Toxoplasmosis

“…IFN-gdependent immune response during the chronic stage suggests ongoing basal inflammation associated with resident cell activation in the CNS (14,15). Upon immunosuppression, the latent infection can reactivate and develop into life-threatening encephalomyelitis (1,6,7,(16)(17)(18).…”