Zika virus (ZIKV) infection may lead to severe neurological consequences, including seizures, and early infancy death. However, the involved mechanisms are still largely unknown. TRPC channels play an important role in regulating nervous system excitability and are implicated in seizure development. We investigated whether TRPCs might be involved in the pathogenesis of ZIKV infection. We found that ZIKV infection increases TRPC4 expression in host cells via the interaction between the ZIKV-NS3 protein and CaMKII, enhancing TRPC4-mediated calcium influx. Pharmacological inhibition of CaMKII decreased both pCREB and TRPC4 protein levels, whereas the suppression of either TRPC4 or CaMKII improved the survival rate of ZIKV-infected cells and reduced viral protein production, likely by impeding the replication phase of the viral life cycle. TRPC4 or CaMKII inhibitors also reduced seizures and increased the survival of ZIKV-infected neonatal mice and blocked the spread of ZIKV in brain organoids derived from human-induced pluripotent stem cells. These findings suggest that targeting CaMKII or TRPC4 may offer a promising approach for developing novel anti-ZIKV therapies, capable of preventing ZIKV-associated seizures and death.

中文翻译：

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在体外和体内抑制宿主 TRPC4 通道可减弱寨卡病毒感染。


寨卡病毒 (ZIKV) 感染可能会导致严重的神经系统后果，包括癫痫发作和婴儿早期死亡。然而，所涉及的机制仍然很大程度上未知。 TRPC 通道在调节神经系统兴奋性中发挥重要作用，并与癫痫发作的发展有关。我们研究了 TRPC 是否可能参与 ZIKV 感染的发病机制。我们发现，ZIKV 感染通过 ZIKV-NS3 蛋白和 CaMKII 之间的相互作用增加宿主细胞中 TRPC4 的表达，从而增强 TRPC4 介导的钙内流。 CaMKII 的药理学抑制可降低 pCREB ​​和 TRPC4 蛋白水平，而 TRPC4 或 CaMKII 的抑制可提高 ZIKV 感染细胞的存活率并减少病毒蛋白的产生，这可能是通过阻碍病毒生命周期的复制阶段来实现的。 TRPC4 或 CaMKII 抑制剂还可以减少癫痫发作，提高感染 ZIKV 的新生小鼠的存活率，并阻止 ZIKV 在源自人类诱导多能干细胞的脑类器官中的传播。这些发现表明，靶向 CaMKII 或 TRPC4 可能为开发新型抗 ZIKV 疗法提供一种有前途的方法，能够预防 ZIKV 相关的癫痫发作和死亡。