Human cytomegalovirus infection impairs axon formation via repressing glycogen synthase kinase-3β activity-mediated adenosine triphosphate synthesis

Human cytomegalovirus (HCMV)has a global distribution and is highly prevalent. HCMV infection has been recognized as a major contributor to neural development abnormalities in embryos and children. However, the underlying mechanisms by which HCMV infection leads to neurological diseases remain incompletely understood. Our study showed that HCMV inhibits neural cell differentiation by affecting the production of adenosine triphosphate (ATP) during neural differentiation. In this work, we found that HCMV infection interferes with the neural differentiation of stem cells from human exfoliated deciduous teeth (SHEDs)and human neuroblastoma cell line (SH-SY5Ys), affects the expression of neural cell markers, and inhibits the axon formation of neural cells. Under neurogenic inductive conditions, HCMV infection of SHEDs and SH-SY5Ys caused an increase in Glycogen synthase kinase-3β(GSK-3β) phosphorylation level and a decrease in GSK-3β phosphatase activity. HCMV infection was shown to inhibits GSK-3β activity, suppresses the level of mitochondrial oxidative phosphorylation in cells, reduces ATP production, impedes energy supply during neural differentiation, and inhibits neural differentiation. Our study sheds light on a molecular mechanism by which crosstalk between protein phosphorylation and oxidative phosphorylation links HCMV infection and neural differentiation and raises a potential strategy for the therapy of congenital HCMV infection.

人类巨细胞病毒（Human cytomegalovirus, HCMV）具有全球分布特征且感染率极高。该病毒感染已被证实是引发胚胎与儿童神经系统发育异常的重要诱因。然而，人类巨细胞病毒感染导致神经系统疾病的具体分子机制目前尚未完全阐明。本研究发现，人类巨细胞病毒可通过影响神经分化过程中的三磷酸腺苷（adenosine triphosphate, ATP）生成，抑制神经细胞分化。本研究中，我们观察到人类巨细胞病毒感染可干扰人脱落乳牙干细胞（human exfoliated deciduous teeth, SHEDs）与人神经母细胞瘤细胞系（SH-SY5Ys）的神经分化过程，影响神经细胞标志物的表达，并抑制神经细胞轴突的形成。在神经诱导培养条件下，人类巨细胞病毒感染SHEDs与SH-SY5Ys可导致糖原合成酶激酶3β（Glycogen synthase kinase-3β, GSK-3β）的磷酸化水平升高，同时降低GSK-3β的磷酸酶活性。研究证实，人类巨细胞病毒感染可抑制GSK-3β的活性，降低细胞内线粒体氧化磷酸化水平，减少ATP生成，阻碍神经分化过程中的能量供给，最终抑制神经细胞分化。本研究揭示了一种全新的分子机制：蛋白质磷酸化与氧化磷酸化之间的串扰将人类巨细胞病毒感染与神经分化过程联系起来，同时为先天性人类巨细胞病毒感染的治疗提供了潜在的干预策略。