Ngô Huân M, Zhou Ying, Lorenzi Hernan, Wang Kai, Kim Taek-Kyun, Zhou Yong, El Bissati Kamal, Mui Ernest, Fraczek Laura, Rajagopala Seesandra V, Roberts Craig W, Henriquez Fiona L, Montpetit Alexandre, Blackwell Jenefer M, Jamieson Sarra E, Wheeler Kelsey, Begeman Ian J, Naranjo-Galvis Carlos, Alliey-Rodriguez Ney, Davis Roderick G, Soroceanu Liliana, Cobbs Charles, Steindler Dennis A, Boyer Kenneth, Noble A Gwendolyn, Swisher Charles N, Heydemann Peter T, Rabiah Peter, Withers Shawn, Soteropoulos Patricia, Hood Leroy, McLeod Rima
The University of Chicago, Chicago, IL, 60637, USA.
Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611, USA.
Sci Rep. 2017 Sep 13;7(1):11496. doi: 10.1038/s41598-017-10675-6.
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.
三分之一的人终身感染寄生于脑部的原生动物寄生虫——刚地弓形虫。其中约1500万人患有先天性弓形虫病。虽然神经行为疾病与血清反应阳性有关，但因果关系尚未得到证实。为了更好地了解这种寄生虫对人类大脑的影响，我们对受感染的大脑进行了全面的系统分析：我们在受感染人群队列中确定了先天性弓形虫病的易感基因，并发现这些基因在人类大脑中表达。对受感染的人类、原代神经元干细胞和单核细胞进行转录组学和定量蛋白质组学分析，揭示了其对神经发育以及神经、免疫和内分泌网络可塑性的影响。在患病儿童血清中鉴定出反映脑损伤和弓形虫感染的蛋白质和微小RNA生物标志物，支持了这些发现。这些数据使用三种系统生物学方法进行解卷积分析：“轨道解卷积”阐明了连接人类易感基因、生物标志物、蛋白质组和转录组的上游调控途径。“聚类解卷积”揭示了涉及影响脑功能和神经回路过程的可视化蛋白质-蛋白质相互作用簇，包括脂质代谢、白细胞迁移和嗅觉。最后，“疾病解卷积”确定了寄生虫与大脑相互作用与癫痫、运动障碍、阿尔茨海默病和癌症之间的关联。这种“重建-解卷积”逻辑提供了祖细胞增强作用的模板，以及影响人类脑寄生虫病和疾病的组成部分。
