登革病毒复制通过调节ZIP8增强不稳定锌池

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS ACS Applied Bio Materials Pub Date : 2021-10-07 DOI:10.1111/cmi.13395

Aleksha Panwar, Jigme Wangchuk, Meenakshi Kar, Rakesh Lodha, Guruprasad R. Medigeshi

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引用次数: 1

摘要

锌依赖性病毒蛋白依赖于细胞内锌稳态来成功完成感染生命周期。在这里，我们报道了在感染登革病毒(DENV)的肝细胞中，细胞内不稳定锌水平在感染登革病毒(DENV)的早期阶段升高，而在感染紫外线灭活病毒或DENV复制抑制剂的细胞中，这种增加的游离锌被消除，这暗示了锌在病毒RNA复制中的稳态作用。这种游离锌的变化是由锌转运蛋白ZIP8介导的，因为sirna介导的ZIP8的敲低导致游离锌水平的增加被取消，从而导致DENV滴度显著降低，这表明ZIP8在DENV复制的早期阶段起着至关重要的作用。此外，与健康对照相比，游离锌水平升高与登革热患者外周血白细胞中登革热基因组拷贝数高相关，这表明锌稳态在登革热感染中起关键作用。登革热病毒在其RNA复制过程中利用细胞锌稳态。ZIP8在登革热病毒复制过程中上调游离锌水平。登革热患者病毒血症增强与细胞内游离锌升高有关。

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Dengue virus replication enhances labile zinc pools by modulation of ZIP8

Zinc-dependent viral proteins rely on intracellular zinc homeostasis for successful completion of infectious life-cycle. Here, we report that the intracellular labile zinc levels were elevated at early stages of dengue virus (DENV) infection in hepatic cells and this increase in free zinc was abolished in cells infected with UV-inactivated virus or with a DENV replication inhibitor implicating a role for zinc homeostasis in viral RNA replication. This change in free zinc was mediated by zinc transporter, ZIP8, as siRNA-mediated knockdown of ZIP8 resulted in abrogation of increase in free zinc levels leading to significant reduction in DENV titers suggesting a crucial role for ZIP8 in early stages of DENV replication. Furthermore, elevated free zinc levels correlated with high copy numbers of dengue genome in peripheral blood leukocytes obtained from dengue patients compared to healthy controls suggesting a critical role for zinc homeostasis in dengue infection.