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Zika virus causes placental pyroptosis and associated adverse fetal outcomes by activating GSDME

Zikai Zhao, Qi Li, Usama Ashraf, Mengjie Yang, Wenjing Zhu, Zheng Chen, Shengbo Cao, View ORCID ProfileJing Ye
doi: https://doi.org/10.1101/2021.09.21.461218
Zikai Zhao
aState Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
bKey Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
cThe Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430070, China
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Qi Li
aState Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
bKey Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
cThe Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430070, China
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Usama Ashraf
bKey Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
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Mengjie Yang
aState Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
bKey Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
cThe Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430070, China
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Wenjing Zhu
aState Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
bKey Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
cThe Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430070, China
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Zheng Chen
aState Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
bKey Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
cThe Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430070, China
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Shengbo Cao
aState Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
bKey Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
cThe Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430070, China
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  • For correspondence: yej@mail.hzau.edu.cn sbcao@mail.hzau.edu.cn
Jing Ye
aState Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
bKey Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
cThe Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430070, China
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  • ORCID record for Jing Ye
  • For correspondence: yej@mail.hzau.edu.cn sbcao@mail.hzau.edu.cn
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Abstract

Zika virus (ZIKV) can be transmitted from mother to fetus during pregnancy, causing adverse fetal outcomes. Several studies have indicated that ZIKV can damage the fetal brain directly; however, whether the ZIKV-induced maternal placental injury contribute to adverse fetal outcomes are sparsely defined. Here, we discovered that ZIKV causes the pyroptosis of placental cells by activating the executor Gasdermin E (GSDME) in vitro and in vivo. Mechanistically, caspase-8 undergoes activation upon the recognition of 5’ untranslated region of viral RNA by RIG-I, followed by the stimulation of caspase-3 to ultimately escalate the GSDME cleavage. Further analyses revealed that the ablation of GSDME in ZIKV-infected pregnant mice attenuates placental pyroptosis, which consequently confers protection against adverse fetal outcomes. In conclusion, our study unveils a novel mechanism of ZIKV-induced adverse fetal outcomes via causing placental cell pyroptosis, which could be employed for developing new therapies for ZIKV-associated diseases.

Significance statement Several studies have elucidated the link between ZIKV infection and congenital ZIKV syndroms (CZS), but the pathogenesis yet needs further study. Here, we reported a novel pathogenic mechanism of ZIKV which leads to pyroptosis of placental cells through activating the pyroptotic executor GSDME, rather than GSDMD. Upon ZIKV infection, GSDME-mediated pyroptosis damages the structure and function of the placenta, thereby affecting the development of the fetus and contributing to the adverse fetal outcomes. Our study highlights the importance of pyroptotic executor GSDME in regulate ZIKV pathogenicity and further confirms that placental injury caused by ZIKV infection is a key factor for CZS.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted September 22, 2021.
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Zika virus causes placental pyroptosis and associated adverse fetal outcomes by activating GSDME
Zikai Zhao, Qi Li, Usama Ashraf, Mengjie Yang, Wenjing Zhu, Zheng Chen, Shengbo Cao, Jing Ye
bioRxiv 2021.09.21.461218; doi: https://doi.org/10.1101/2021.09.21.461218
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Zika virus causes placental pyroptosis and associated adverse fetal outcomes by activating GSDME
Zikai Zhao, Qi Li, Usama Ashraf, Mengjie Yang, Wenjing Zhu, Zheng Chen, Shengbo Cao, Jing Ye
bioRxiv 2021.09.21.461218; doi: https://doi.org/10.1101/2021.09.21.461218

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