CRISPR screening of porcine sgRNA library identifies host factors associated with Japanese encephalitis virus replication

Changzhi Zhao, Hailong Liu, Tianhe Xiao, Zichang Wang, Xiongwei Nie, Xinyun Li, Ping Qian, Liuxing Qin, Xiaosong Han, Jinfu Zhang, Jinxue Ruan, Mengjin Zhu, Yi-Liang Miao, Bo Zuo, Kui Yang, Shengsong Xie () and Shuhong Zhao ()
Additional contact information
Changzhi Zhao: Huazhong Agricultural University
Hailong Liu: Huazhong Agricultural University
Tianhe Xiao: Huazhong Agricultural University
Zichang Wang: Huazhong Agricultural University
Xiongwei Nie: Huazhong Agricultural University
Xinyun Li: Huazhong Agricultural University
Ping Qian: Huazhong Agricultural University
Liuxing Qin: Huazhong Agricultural University
Xiaosong Han: Huazhong Agricultural University
Jinfu Zhang: Huazhong Agricultural University
Jinxue Ruan: Huazhong Agricultural University
Mengjin Zhu: Huazhong Agricultural University
Yi-Liang Miao: Huazhong Agricultural University
Bo Zuo: Huazhong Agricultural University
Kui Yang: School of Veterinary Medicine
Shengsong Xie: Huazhong Agricultural University
Shuhong Zhao: Huazhong Agricultural University

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Japanese encephalitis virus (JEV) is a mosquito-borne zoonotic flavivirus that causes encephalitis and reproductive disorders in mammalian species. However, the host factors critical for its entry, replication, and assembly are poorly understood. Here, we design a porcine genome-scale CRISPR/Cas9 knockout (PigGeCKO) library containing 85,674 single guide RNAs targeting 17,743 protein-coding genes, 11,053 long ncRNAs, and 551 microRNAs. Subsequently, we use the PigGeCKO library to identify key host factors facilitating JEV infection in porcine cells. Several previously unreported genes required for JEV infection are highly enriched post-JEV selection. We conduct follow-up studies to verify the dependency of JEV on these genes, and identify functional contributions for six of the many candidate JEV-related host genes, including EMC3 and CALR. Additionally, we identify that four genes associated with heparan sulfate proteoglycans (HSPGs) metabolism, specifically those responsible for HSPGs sulfurylation, facilitate JEV entry into porcine cells. Thus, beyond our development of the largest CRISPR-based functional genomic screening platform for pig research to date, this study identifies multiple potentially vulnerable targets for the development of medical and breeding technologies to treat and prevent diseases caused by JEV.

Date: 2020
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DOI: 10.1038/s41467-020-18936-1

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