TY - JOUR
T1 - Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer
AU - Ngô, Huân M.
AU - Zhou, Ying
AU - Lorenzi, Hernan
AU - Wang, Kai
AU - Kim, Taek Kyun
AU - Zhou, Yong
AU - Bissati, Kamal El
AU - Mui, Ernest
AU - Fraczek, Laura
AU - Rajagopala, Seesandra V.
AU - Roberts, Craig W.
AU - Henriquez, Fiona L.
AU - Montpetit, Alexandre
AU - Blackwell, Jenefer M.
AU - Jamieson, Sarra E.
AU - Wheeler, Kelsey
AU - Begeman, Ian J.
AU - Naranjo-Galvis, Carlos
AU - Alliey-Rodriguez, Ney
AU - Davis, Roderick G.
AU - Soroceanu, Liliana
AU - Cobbs, Charles
AU - Steindler, Dennis A.
AU - Boyer, Kenneth
AU - Noble, A. Gwendolyn
AU - Swisher, Charles N.
AU - Heydemann, Peter T.
AU - Rabiah, Peter
AU - Withers, Shawn
AU - Soteropoulos, Patricia
AU - Hood, Leroy
AU - McLeod, Rima
N1 - Funding Information:
We gratefully acknowledge P. Meier for his earlier contributions to the NCCCTS, Theodore Karrison and Kristen Wroblewski for their ongoing assistance with analysis of the NCCCTS, T. Conrad Gilliam for his interest and support as this work was being completed, Wayne Andersen's critical reading of the manuscript and suggestions and support of the L-NSC proteomics through the CSGID, and Aubrey Hargrave for her contribution to early genetics work. We gratefully acknowledge Mariane Melo and Jeroen Saeij’s helpful early discussions about methodology of infection of cells for transcriptomics and interpretation of patterns observed. We appreciate the helpful suggestions of Elisabetta Sabini, PhD, during the preparation of this manuscript. This work was funded by Grant numbers R01 AI027530, R01 AI071319, U01 AI077887, and U01 AI082180 from NIH NIAID DMID and by the Mann Cornwell Family, the Engel family and “Taking out Toxo”, the Rooney, Drago, and the Morel families. Research reported in this publication also was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Contract Numbers HHSN272200900007C, HHSN272200700058C, and HHSN272201200026C and Award Number U19AI110819. The team at the Institute for Systems Biology is partially supported by research contracts from DTRA and DOD (HDTRA1-13-C-0055, W911NF-09-D0001 and W911SR-07-C0101). Content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Proteomics and informatics services for L-NSC were performed at CBC-UIC Research Resources Center Mass Spectrometry, Metabolomics, and Proteomics Facility established in part by a grant from Searle Funds at the Chicago Community trust to the Chicago Biomedical Consortium.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41598-017-10675-6
DO - 10.1038/s41598-017-10675-6
M3 - Article
C2 - 28904337
AN - SCOPUS:85029295393
SN - 2045-2322
VL - 7
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 11496
ER -