Nature | Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer
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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.
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