2. Academic Validation
  3. Targeting the Inositol-Requiring Enzyme-1 Pathway Efficiently Reverts Zika Virus-Induced Neurogenesis and Spermatogenesis Marker Perturbations

Targeting the Inositol-Requiring Enzyme-1 Pathway Efficiently Reverts Zika Virus-Induced Neurogenesis and Spermatogenesis Marker Perturbations

  • ACS Infect Dis. 2020 Jul 10;6(7):1745-1758. doi: 10.1021/acsinfecdis.9b00526.
Hin Chu 1 2,  Terrence T T Yuen 1 2,  Kenn K H Chik 2,  Shuofeng Yuan 1 2,  Huiping Shuai 1 2,  Zijiao Zou 2,  Yixin Wang 2,  Zheng Zhu 2,  Dong Yang 2,  Vincent K M Poon 2,  Chris C S Chan 2,  Jie Zhou 1 2,  Feifei Yin 3 4 5,  Kin-Hang Kok 1 2,  Kwok-Yung Yuen 1 2 3 4 6 7,  Jasper F W Chan 1 2 3 4 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region 999077, China.
  • 2 Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region 999077, China.
  • 3 Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Hainan Medical University and The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region 999077, China.
  • 4 Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University, Haikou, Hainan 571199, China.
  • 5 Department of Pathogen Biology, Hainan Medical University, Haikou, Hainan 571199, China.
  • 6 Carol Yu Centre for Infection, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region 999077, China.
  • 7 Department of Clinical Microbiology and Infection Control, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong 518053, China.
PMID: 32329611 DOI: 10.1021/acsinfecdis.9b00526
Abstract

Zika virus (ZIKV) is an emerging Flavivirus that may be associated with congenital anomalies in infected fetuses and severe neurological and genital tract complications in infected adults. Currently, Antiviral treatments to revert these ZIKV-induced complications are lacking. ZIKV Infection has recently been suggested to upregulate the host unfolded protein response, which may contribute to the congenital neurological anomalies. As an extension from these findings, we thoroughly investigated the ZIKV-induced unfolded protein response using a combination of the neuronal cell line, induced pluripotent stem cell-derived human neuronal stem and progenitor cells, and an interferon receptor-deficient A129 mouse model. Our results revealed a critical contribution of the inositol-requiring enzyme-1 (IRE1) arm of the unfolded protein response to ZIKV-induced neurological and testicular complications. Importantly, the inhibition of the IRE1 signaling pathway activation with KIRA6 (kinase-inhibiting RNAse attenuator 6), a selective small molecule IRE1 Inhibitor that promotes cell survival, potently reverted the ZIKV-induced perturbations of the key gene expressions associated with neurogenesis and spermatogenesis in vitro and in vivo, highlighting the potential of IRE1 inhibition as a novel host-targeting Antiviral strategy in combating against ZIKV-induced neurological and testicular pathologies.

Keywords

IRE1; UPR; Zika virus; neurogenesis; spermatogenesis.

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