Zinc supplementation in cell culture has been shown to inhibit various viruses, like herpes simplex virus, rotavirus, severe acute respiratory syndrome (SARS) coronavirus, rhinovirus, and respiratory syncytial virus (RSV). However, whether zinc plays a direct antiviral role in viral infections and whether viruses have adopted strategies to modulate zinc homeostasis have not been investigated. Results from clinical trials of zinc supplementation in infections indicate that zinc supplementation may be beneficial in a pathogen- or disease-specific manner, further underscoring the importance of understanding the interaction between zinc homeostasis and virus infections at the molecular level. We investigated the effect of RSV infection on zinc homeostasis and show that RSV infection in lung epithelial cells leads to modulation of zinc homeostasis. The intracellular labile zinc pool increases upon RSV infection in a multiplicity of infection (MOI)-dependent fashion. Small interfering RNA (siRNA)-mediated knockdown of the ubiquitous zinc uptake transporter ZIP1 suggests that labile zinc levels are increased due to the increased uptake by RSV-infected cells as an antiviral response. Adding zinc to culture medium after RSV infection led to significant inhibition of RSV titers, whereas depletion of zinc by a zinc chelator, N,N,N′,N′-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN) led to an increase in RSV titers. The inhibitory effect of zinc was specific, as other divalent cations had no effect on RSV titers. Both RSV infection and zinc chelation by TPEN led to reactive oxygen species (ROS) induction, whereas addition of zinc blocked ROS induction. These results suggest a molecular link between RSV infection, zinc homeostasis, and oxidative-stress pathways and provide new insights for developing strategies to counter RSV infection.

中文翻译：

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呼吸道合胞病毒诱导的氧化应激导致肺上皮细胞中不稳定的锌库增加。

在细胞培养中补充锌已显示出抑制各种病毒的能力，例如单纯疱疹病毒，轮状病毒，严重急性呼吸系统综合症（SARS）冠状病毒，鼻病毒和呼吸道合胞病毒（RSV）。但是，锌是否在病毒感染中起直接抗病毒作用，以及病毒是否已采用调节锌稳态的策略尚未得到研究。感染中补充锌的临床试验结果表明，补充锌可能以病原体或疾病特异性的方式有益，这进一步强调了在分子水平上了解锌稳态与病毒感染之间相互作用的重要性。我们调查了RSV感染对锌稳态的影响，并表明肺上皮细胞中的RSV感染导致锌稳态的调节。RSV感染后，细胞内不稳定锌池以多种感染（MOI）依赖性方式增加。小干扰RNA（siRNA）介导的普遍存在的锌摄取转运蛋白的敲低ZIP1表明，不稳定的锌水平增加是由于RSV感染细胞作为抗病毒应答而增加的摄取。RSV感染后向培养基中添加锌会显着抑制RSV滴度，而锌螯合剂N，N，N '，N会耗尽锌′-四（2-吡啶基甲基）-1，2-乙二胺（TPEN）导致RSV滴度增加。锌的抑制作用是特异性的，因为其他二价阳离子对RSV效价没有影响。TPEN引起的RSV感染和锌螯合均导致活性氧（ROS）诱导，而锌的添加会阻止ROS诱导。这些结果表明，RSV感染，锌稳态和氧化应激途径之间存在分子联系，并为制定应对RSV感染的策略提供了新见识。