2. Academic Validation
  3. In vitro and in vivo inhibition of the host TRPC4 channel attenuates Zika virus infection

In vitro and in vivo inhibition of the host TRPC4 channel attenuates Zika virus infection

  • EMBO Mol Med. 2024 Jul 15. doi: 10.1038/s44321-024-00103-4.
Xingjuan Chen # 1 2,  Yunzheng Yan # 2,  Zhiqiang Liu # 3,  Shaokang Yang # 2,  Wei Li 2,  Zhuang Wang 1,  Mengyuan Wang 1,  Juan Guo 1,  Zhenyang Li 2,  Weiyan Zhu 2,  Jingjing Yang 2 4,  Jiye Yin 2,  Qingsong Dai 2,  Yuexiang Li 2,  Cui Wang 3,  Lei Zhao 2,  Xiaotong Yang 2,  Xiaojia Guo 2,  Ling Leng 5,  Jiaxi Xu 6,  Alexander G Obukhov 7,  Ruiyuan Cao 8,  Wu Zhong 9
Affiliations

Affiliations

  • 1 Institute of Medical Research, Northwestern Polytechnical University, 710072, Xi'an, Shanxi, China.
  • 2 National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
  • 3 Beijing Institute of Basic Medical Sciences, Beijing, China.
  • 4 School of Pharmaceutical Sciences, Hainan University, Haikou, China.
  • 5 State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 6 Department of Physiology and Pathophysiology, Xi'an Jiaotong University Health Science Center, 710061, Xi'an, Shanxi, China.
  • 7 The Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. aobukhov@iu.edu.
  • 8 National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, China. caoruiyuan@bmi.ac.cn.
  • 9 National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, China. zhongwu@bmi.ac.cn.
  • # Contributed equally.
PMID: 39009885 DOI: 10.1038/s44321-024-00103-4
Abstract

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.

Keywords

Antiviral Target; Calcium; Epilepsy; TRPC4 Channel; Zika Virus.

Figures
Products