Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer

Abstract

One third of humans are infected lifelong with the brain-dwelling, protozoan parasite, Toxoplasma gondii. Approximately fifteen million of these have congenital toxoplasmosis. Although neurobehavioral disease is associated with seropositivity, causality is unproven. To better understand what this parasite does to human brains, we performed a comprehensive systems analysis of the infected brain: We identified susceptibility genes for congenital toxoplasmosis in our cohort of infected humans and found these genes are expressed in human brain. Transcriptomic and quantitative proteomic analyses of infected human, primary, neuronal stem and monocytic cells revealed effects on neurodevelopment and plasticity in neural, immune, and endocrine networks. These findings were supported by identification of protein and miRNA biomarkers in sera of ill children reflecting brain damage and T. gondii infection. These data were deconvoluted using three systems biology approaches: “Orbital-deconvolution” elucidated upstream, regulatory pathways interconnecting human susceptibility genes, biomarkers, proteomes, and transcriptomes. “Cluster-deconvolution” revealed visual protein-protein interaction clusters involved in processes affecting brain functions and circuitry, including lipid metabolism, leukocyte migration and olfaction. Finally, “disease-deconvolution” identified associations between the parasite-brain interactions and epilepsy, movement disorders, Alzheimer’s disease, and cancer. This “reconstruction-deconvolution” logic provides templates of progenitor cells’ potentiating effects, and components affecting human brain parasitism and diseases.

LatentToxoplasma gondiiinfection increases soluble mutant huntingtin and promotes neurodegeneration in the YAC128 mouse model of Huntington’s disease

“…Despite this caveat, our study provides proof of principle that chronic latent toxoplasmosis in HD mice potentiates established markers of HD progression. Interestingly, a recent study reported that early--life infection with T. gondii alters a wide array of human genes and pathways implicated in the pathogenesis of neurological disorders including HD, Alzheimer's disease, and seizure disorders [61]. In humans, the prevalence of T. gondii increases with age [6,62].…”

Downregulation of the Central Noradrenergic System by Toxoplasma gondii Infection

“…This might not have been identified in transcriptomic studies published of whole infected brain tissue, which principally identified changes in expression of host immune response genes with the mixture of cell types in the brain (27,28). A recent transcriptomic study by Ngô et al (73) identified differentially expressed genes after only 18 h of infection (i.e., during vegetative replication stages) in neural stem cells that expressed a range of markers for structural proteins found among different types of neurons and astrocytes. Hence, those results are difficult to compare with our approach using neuronal cells that are fully functional in synthesis and release (with potassium activation) of DA and NE to investigate changes in expression of neuronal genes.…”

Seasonal and spatial variation in Toxoplasma gondii contamination in soil in urban public spaces in California, United States

“…Toxoplasma gondii infection can cause miscarriage when women are first exposed during pregnancy, severe ocular and neurological lesions in newborns and systemic disease and deaths in immunocompromised individuals (Maenz et al, ; Sukthana, ; Torgerson & Mastroiacovo, ). Infection has also been associated with schizophrenia and neurodegenerative diseases in congenitally infected people (Brown et al, ; Ngô et al, ). Although less common, severe health outcomes in immunocompetent individuals following acquired infection with certain strains of T. gondii have also been reported and include ocular toxoplasmosis, pneumonia, organ failure and death (Carme, Demar, Ajzenberg, & Dardé, ; Cortés & Aguirre, ; Glasner et al, ; Leal et al, ).…”