Puig-Pijuan Teresa, Souza Leticia R Q, Pedrosa Carolina da S G, Higa Luiza M, Monteiro Fabio Luis, Tanuri Amilcar, Valverde Rafael H F, Einicker-Lamas Marcelo, Rehen Stevens Kastrup
D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil.
Laboratory of Biomembranes, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
J Cell Biochem. 2022 Dec;123(12):1997-2008. doi: 10.1002/jcb.30323. Epub 2022 Sep 5.
The Zika virus (ZIKV) caused neurological abnormalities in more than 3500 Brazilian newborns between 2015 and 2020. Data have pointed to oxidative stress in astrocytes as well as to dysregulations in neural cell proliferation and cell cycle as important events accounting for the cell death and neurological complications observed in Congenital Zika Syndrome. Copper imbalance has been shown to induce similar alterations in other pathologies, and disturbances in copper homeostasis have already been described in viral infections. Here, we investigated copper homeostasis imbalance as a factor that could contribute to the cytotoxic effects of ZIKV infection in astrocytes. Human induced pluripotent stem cell-derived astrocytes were infected with ZIKV; changes in the gene expression of copper homeostasis proteins were analyzed. The effect of the administration of CuCl or a copper chelator on oxidative stress, cell viability and percentage of infection were also studied. ZIKV infection leads to a downregulation of one of the transporters mediating copper release, ATP7B protein. We also observed the activation of mechanisms that counteract high copper levels, including the synthesis of copper chaperones and the reduction of the copper importer protein CTR1. Finally, we show that chelator-mediated copper sequestration in ZIKV-infected astrocytes reduces the levels of reactive oxygen species and improves cell viability, but does not change the overall percentage of infected cells. In summary, our results show that copper homeostasis imbalance plays a role in the pathology of ZIKV in astrocytes, indicating that it may also be a factor accounting for the developmental abnormalities in the central nervous system following viral infection. Evaluating micronutrient levels and the use of copper chelators in pregnant women susceptible to ZIKV infection may be promising strategies to manage novel cases of congenital ZIKV syndrome.
2015年至2020年间，寨卡病毒（ZIKV）在3500多名巴西新生儿中引发了神经功能异常。数据表明，星形胶质细胞中的氧化应激以及神经细胞增殖和细胞周期的失调是导致先天性寨卡综合征中细胞死亡和神经并发症的重要因素。铜失衡已被证明在其他病理过程中会引发类似变化，并且在病毒感染中也已发现铜稳态受到干扰。在此，我们研究了铜稳态失衡作为可能导致ZIKV感染星形胶质细胞产生细胞毒性作用的一个因素。用ZIKV感染人诱导多能干细胞衍生的星形胶质细胞；分析铜稳态蛋白基因表达的变化。还研究了施用CuCl或铜螯合剂对氧化应激、细胞活力和感染百分比的影响。ZIKV感染导致介导铜释放的转运蛋白之一ATP7B蛋白表达下调。我们还观察到对抗高铜水平机制的激活，包括铜伴侣蛋白的合成以及铜导入蛋白CTR1的减少。最后，我们表明在ZIKV感染的星形胶质细胞中，螯合剂介导的铜螯合可降低活性氧水平并提高细胞活力，但不会改变被感染细胞的总体百分比。总之，我们的结果表明铜稳态失衡在ZIKV感染星形胶质细胞的病理过程中起作用，这表明它可能也是病毒感染后中枢神经系统发育异常的一个因素。评估易感染ZIKV的孕妇的微量营养素水平以及使用铜螯合剂可能是管理先天性ZIKV综合征新病例的有前景的策略。
