Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer

Sci Rep. 2017 Sep 13;7(1):11496. doi: 10.1038/s41598-017-10675-6.

Ngô HM^1,2,3, Zhou Y¹, Lorenzi H⁴, Wang K⁵, Kim TK⁵, Zhou Y⁵, Bissati KE¹, Mui E¹, Fraczek L¹, Rajagopala SV⁴, Roberts CW⁶, Henriquez FL^1,7, Montpetit A⁸, Blackwell JM^9,10, Jamieson SE¹⁰, Wheeler K¹, Begeman IJ¹, Naranjo-Galvis C¹, Alliey-Rodriguez N¹, Davis RG¹¹, Soroceanu L¹², Cobbs C¹², Steindler DA¹³, Boyer K¹⁴, Noble AG², Swisher CN², Heydemann PT¹⁴, Rabiah P¹⁵, Withers S¹, Soteropoulos P¹⁶, Hood L⁵, McLeod R¹⁷.

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.

PMID:

28904337

DOI:

10.1038/s41598-017-10675-6