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

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

Author information

1
The University of Chicago, Chicago, IL, 60637, USA.
2
Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611, USA.
3
BrainMicro LLC, New Haven, CT, 06511, USA.
4
J Craig Venter Institute, Rockville, MD, 20850, USA.
5
Institute for Systems Biology, Seattle, WA, 98109, USA.
6
University of Strathclyde, Glasgow, G1 1XQ, United Kingdom.
7
FLH, IBEHR School of Science and Sport, University of the West of Scotland, Paisley, PA1 2BE, UK.
8
Genome Quebec, Montréal, QC H3B 1S6, Canada; McGill University, Montréal, QC H3A 0G4, Canada.
9
Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, United Kingdom.
10
Telethon Kids Institute, The University of Western Australia, Perth, Australia.
11
University of Illinois-Chicago, Chicago, IL, 60607, USA.
12
California Pacific Medical Center, San Francisco, CA, 94114, USA.
13
JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, 02111, USA.
14
Rush University Medical Center, Chicago, IL, 60612, USA.
15
Northshore University Health System, Evanston, IL, 60201, USA.
16
Rutgers University, Newark, New Jersey, 07101, USA.
17
The University of Chicago, Chicago, IL, 60637, USA. rmcleod@uchicago.edu.

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.

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