Omics/Systems Biology (September 2017)
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.
Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer
Medicines. Compounds Structure function, anti-sense
Molecular target identification and inhibition with small molecules or antisense: Left Panel:.Phosphoglyceromutase(PGM) is a novel antimivrobial target identified with Northwestern pipeline for crystallography,CRISP and PPMO analyses. Middle panel: Anti-sense (eg, Vivo Morpholino) is also an effective means to inhibit the parasite. Right panel: Brazilian parasite with a cyst phenotype in vitro, causes changes in primary human neuronal cells that are similar to those associated with neurodegenerative diseases. Cytochrome B is one of the genes highly expressed in this parasite. Cytochrome b qi domain was targeted with compounds with novel scaffold that improve solubility. The 1st lead compound substantially reduces the number of dormant parasites in tissue culture and mice. Co crystallization provides insight in to how to develop these novel scaffolds into medicinesEGS parasite growing in tissue culture as cyst like organism containing slow growing bradyzoite like organism in left panel, and eliminate organisms following treatment with a cytochrome b Qi domain inhibitor
Delivery of antimicrobials into parasites
CSGID Solves Structures and Identifies Phenotypes for Five Enzymes in Toxoplasma gondii
Special Student Accomplishments toward a curative medicine include high school, undergraduate, medical student and post doctoral fellows
Sarah Dovgin graduated from the Illinois Mathematics and Science Academy (IMSA). She worked with Dr. McLeod and the toxoplasmosis team for several years through IMSA’s Student Inquiry and Research program. She worked with peptide phosphorodiamidate morpholino oligomer (PPMO) project, the ornithine aminotransferase (OAT) project, and the cytochrome b project. She won 1st place for her poster at the 2015 International Student Science Fair (ISSF) in Melbourne, Australia. Sarah now attends Case Western Reserve University studying Biomedical Engineering and computer science.
