Fujimura Kimino, Guise Amanda J, Nakayama Tojo, Schlaffner Christoph N, Meziani Anais, Kumar Mukesh, Cheng Long, Vaughan Dylan J, Kodani Andrew, Van Haren Simon, Parker Kenneth, Levy Ofer, Durbin Ann F, Bosch Irene, Gehrke Lee, Steen Hanno, Mochida Ganeshwaran H, Steen Judith A
F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Division of Genetics and Genomics and The Manton Center for Orphan Disease, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
iScience. 2023 May 19;26(7):106909. doi: 10.1016/j.isci.2023.106909. eCollection 2023 Jul 21.
Characterizing perturbation of molecular pathways in congenital Zika virus (ZIKV) infection is critical for improved therapeutic approaches. Leveraging integrative systems biology, proteomics, and RNA-seq, we analyzed embryonic brain tissues from an immunocompetent, wild-type congenital ZIKV infection mouse model. ZIKV induced a robust immune response accompanied by the downregulation of critical neurodevelopmental gene programs. We identified a negative correlation between ZIKV polyprotein abundance and host cell cycle-inducing proteins. We further captured the downregulation of genes/proteins, many of which are known to be causative for human microcephaly, including Eomesodermin/T-box Brain Protein 2 (EOMES/TBR2) and Neuronal Differentiation 2 (NEUROD2). Disturbances of distinct molecular pathways in neural progenitors and post-mitotic neurons may contribute to complex brain phenotype of congenital ZIKV infection. Overall, this report on protein- and transcript-level dynamics enhances understanding of the ZIKV immunopathological landscape through characterization of fetal immune response in the developing brain.
明确先天性寨卡病毒（ZIKV）感染中分子通路的扰动情况对于改进治疗方法至关重要。利用整合系统生物学、蛋白质组学和RNA测序技术，我们分析了来自具有免疫能力的野生型先天性ZIKV感染小鼠模型的胚胎脑组织。ZIKV引发了强烈的免疫反应，同时关键神经发育基因程序下调。我们发现ZIKV多聚蛋白丰度与宿主细胞周期诱导蛋白之间呈负相关。我们进一步捕捉到了基因/蛋白质的下调，其中许多已知是导致人类小头畸形的原因，包括胚外中胚层决定因子/T盒脑蛋白2（EOMES/TBR2）和神经分化蛋白2（NEUROD2）。神经祖细胞和有丝分裂后神经元中不同分子通路的紊乱可能导致先天性ZIKV感染的复杂脑表型。总体而言，这份关于蛋白质和转录水平动态变化的报告通过对发育中大脑胎儿免疫反应的表征，增强了对ZIKV免疫病理格局的理解。
