McDougall William M, Perreira Jill M, Hung Hui-Fang, Vertii Anastassiia, Xiaofei E, Zimmerman Wendy, Kowalik Timothy F, Doxsey Stephen, Brass Abraham L
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda, Bethesda, MD 20814, USA.
iScience. 2019 Feb 22;12:270-279. doi: 10.1016/j.isci.2019.01.025. Epub 2019 Jan 21.
Congenital microcephaly occurs in utero during Zika virus (ZIKV) infection. The single-gene disorder, Majewski osteodysplastic primordial dwarfism type II (MOPDII), also leads to microcephaly and is concomitant with a decrease in the centrosomal protein, pericentrin (PCNT). This protein is a known contributor of mitotic spindle misorientation and ultimately, microcephaly. Similar to MOPDII, either viral infection or interferon (IFN)-α exposure reduced PCNT levels at the mitotic spindle poles. We unexpectedly found that infection of cells with any one of a diverse set of viruses, such as ZIKV, dengue virus, cytomegalovirus, influenza A virus, or hepatitis B virus, or treatment of cells with the anti-viral cytokine, IFN-α, produced mitotic spindle misorientation. These findings demonstrate a related mechanism for the development of microcephaly in viral infection, the host's antiviral IFN response, and primordial dwarfism.
先天性小头畸形发生在子宫内寨卡病毒（ZIKV）感染期间。单基因疾病II型马耶夫斯基骨发育异常原发性侏儒症（MOPDII）也会导致小头畸形，并且伴随着中心体蛋白中心粒外周蛋白（PCNT）水平的降低。这种蛋白质是已知的有丝分裂纺锤体方向错误的促成因素，最终导致小头畸形。与MOPDII相似，病毒感染或干扰素（IFN）-α暴露会降低有丝分裂纺锤体两极的PCNT水平。我们意外地发现，用多种病毒中的任何一种感染细胞，如寨卡病毒、登革热病毒、巨细胞病毒、甲型流感病毒或乙型肝炎病毒，或用抗病毒细胞因子IFN-α处理细胞，都会导致有丝分裂纺锤体方向错误。这些发现证明了病毒感染、宿主抗病毒IFN反应和原发性侏儒症中小头畸形发展的相关机制。
