GGCX promotes Eurasian avian-like H1N1 swine influenza virus adaption to interspecies receptor binding

Jiahui Zou, Meijun Jiang, Rong Xiao, Huimin Sun, Hailong Liu, Thomas Peacock, Shaoyu Tu, Tong Chen, Jinli Guo, Yaxin Zhao, Wendy Barclay (), Shengsong Xie () and Hongbo Zhou ()
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Jiahui Zou: Huazhong Agricultural University
Meijun Jiang: Huazhong Agricultural University
Rong Xiao: Huazhong Agricultural University
Huimin Sun: Huazhong Agricultural University
Hailong Liu: Huazhong Agricultural University
Thomas Peacock: Imperial College London
Shaoyu Tu: Huazhong Agricultural University
Tong Chen: Huazhong Agricultural University
Jinli Guo: Huazhong Agricultural University
Yaxin Zhao: Huazhong Agricultural University
Wendy Barclay: Imperial College London
Shengsong Xie: Huazhong Agricultural University
Hongbo Zhou: Huazhong Agricultural University

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract The Eurasian avian-like (EA) H1N1 swine influenza virus (SIV) possesses the capacity to instigate the next influenza pandemic, owing to its heightened affinity for the human-type α-2,6 sialic acid (SA) receptor. Nevertheless, the molecular mechanisms underlying the switch in receptor binding preferences of EA H1N1 SIV remain elusive. In this study, we conduct a comprehensive genome-wide CRISPR/Cas9 knockout screen utilizing EA H1N1 SIV in porcine kidney cells. Knocking out the enzyme gamma glutamyl carboxylase (GGCX) reduces virus replication in vitro and in vivo by inhibiting the carboxylation modification of viral haemagglutinin (HA) and the adhesion of progeny viruses, ultimately impeding the replication of EA H1N1 SIV. Furthermore, GGCX is revealed to be the determinant of the D225E substitution of EA H1N1 SIV, and GGCX-medicated carboxylation modification of HA 225E contributes to the receptor binding adaption of EA H1N1 SIV to the α-2,6 SA receptor. Taken together, our CRISPR screen has elucidated a novel function of GGCX in the support of EA H1N1 SIV adaption for binding to α-2,6 SA receptor. Consequently, GGCX emerges as a prospective antiviral target against the infection and transmission of EA H1N1 SIV.

Date: 2025
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DOI: 10.1038/s41467-025-55903-0

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