Institute of Medical Research, Northwestern Polytechnical University, 710072, Xi'an, Shanxi, China.
National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
EMBO Mol Med. 2024 Aug;16(8):1817-1839. doi: 10.1038/s44321-024-00103-4. Epub 2024 Jul 15.
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.
寨卡病毒（ZIKV）感染可能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，其涉及的机制在很大程度上仍不清楚。瞬时受体电位通道（TRPC）在调节神经系统兴奋性方面发挥着重要作用，并与癫痫发作的发展有关。我们研究了 TRPC 是否可能参与寨卡病毒感染的发病机制。我们发现寨卡病毒感染通过寨卡病毒 NS3 蛋白与钙调蛋白依赖性蛋白激酶 II（CaMKII）的相互作用，增加宿主细胞中 TRPC4 的表达，增强 TRPC4 介导的钙离子内流。CaMKII 的药理学抑制作用降低了 pCREB 和 TRPC4 蛋白水平，而抑制 TRPC4 或 CaMKII 均可提高寨卡病毒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 抑制剂还减少了癫痫发作，提高了寨卡病毒感染的新生小鼠的存活率，并阻止了寨卡病毒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 可能为开发新型抗寨卡病毒疗法提供一种有前途的方法，能够预防寨卡病毒相关的癫痫发作和死亡。
