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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #355102
Title: Toxoplasma modulates signature pathways of human epilepsy, neurodegeneration and cancer

Author
item NGO, HUAN - University Of Chicago
item ZHOU, YING - University Of Chicago
item LORENZI, HERNAN - J Craig Venter Institute
item WANG, KAI - Institute For Systems Biology
item KIM, TAEK-KYUN - Institute For Systems Biology
item ZHOU, YONG - Institute For Systems Biology
item EL BISSATI, KAMAL - University Of Chicago
item MUI, ERNEST - University Of Chicago
item FRACZEK, LAURA - University Of Chicago
item RAJAGOPALA, SEESANDRA - J Craig Venter Institute
item ROBERTS, CRAIG - University Of Strathclyde
item HENRIQUEZ, FIONA - University Of Chicago
item MONTPETIT, ALEXANDRE - Genome Quebec
item BLACKWELL, JENEFER - University Of Cambridge
item JAMIESON, SARRA - University Of Western Australia
item WHEELER, KELSEY - University Of Chicago
item BEGEMAN, IAN - University Of Chicago
item NARANJO-GALVIS, CARLOS - University Of Chicago
item ALLIEY-RODRIGUEZ, NEY - University Of Chicago
item DAVIS, RODERICK - University Of Illinois
item SOROCEANU, LILIANA - California Pacific Medical Center
item COBBS, CHARLES - California Pacific Medical Center
item STEINDLER, DENNIS - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item BOYER, KENNETH - Rush University Medical Center
item NOBLE, A. GWENDOLYN - Northwestern University
item SWISHER, CHARLES - Northwestern University
item HEYDEMANN, PETER - Rush University Medical Center
item RABIAH, PETER - Northshore University Health System
item WITHERS, SHAWN - University Of Chicago
item SOTEROPOULOS, PATRICIA - Rutgers University
item HOOD, LEROY - Institute For Systems Biology
item MCLEOD, RIMA - University Of Chicago

Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/14/2017
Publication Date: 9/13/2017
Citation: Ngo, H.M., Zhou, Y., Lorenzi, H., Wang, K., Kim, T., Zhou, Y., El Bissati, K., Mui, E., Fraczek, L., Rajagopala, S.V., Roberts, C.W., Henriquez, F.L., Montpetit, A., Blackwell, J.M., Jamieson, S.E., Wheeler, K., Begeman, I.J., Naranjo-Galvis, C., Alliey-Rodriguez, N., Davis, R.G., Soroceanu, L., Cobbs, C., Steindler, D., Boyer, K., Noble, A., Swisher, C.N., Heydemann, P.T., Rabiah, P., Withers, S., Soteropoulos, P., Hood, L., McLeod, R. 2017. Toxoplasma modulates signature pathways of human epilepsy, neurodegeneration and cancer. Scientific Reports. 7(1):11496. https://doi.org/10.1038/s41598-017-10675-6.
DOI: https://doi.org/10.1038/s41598-017-10675-6

Interpretive Summary: One third to one half of all humans are infected with the brain-dwelling, protozoan parasite Toxoplasma gondii for their entire lives. Approximately fifteen million of these people have congenital toxoplasmosis. The relationship between infection and some of the brain behavioral changes that accompany it are not fully understood. In order to better understand what this parasite does to human brains, we performed a comprehensive systems analysis of the infected brain and characterized changes in the genome that are associated with risk for some of these brain changes following infection. This work was done focusing on susceptibility genes in our cohort of infected humans and found these genes are expressed in the human brain. Systems biology analysis of genetic networks that changed following T. gondii infection in a population of human neural stem cells showed pathways that are also involved in neurodegenerative disease (e.g. Parkinson's and Alzheimer's) and cancer. Future studies will explore standard of care and novel approaches for targeting these pathways for protection following infection.

Technical 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.