Mutual antagonism of mouse-adaptation mutations in HA and PA proteins on H9N2 virus replication

Liping Ma; Huabin Zheng; Xianliang Ke; Rui Gui; Zhongzi Yao; Jiasong Xiong; Quanjiao Chen

doi:10.1016/j.virs.2023.11.004

February 2024

Citation: Liping Ma, Huabin Zheng, Xianliang Ke, Rui Gui, Zhongzi Yao, Jiasong Xiong, Quanjiao Chen. Mutual antagonism of mouse-adaptation mutations in HA and PA proteins on H9N2 virus replication .VIROLOGICA SINICA, 2024, 39(1) : 56-70. http://dx.doi.org/10.1016/j.virs.2023.11.004

Mutual antagonism of mouse-adaptation mutations in HA and PA proteins on H9N2 virus replication

Liping Ma ^a,b,d ,
Huabin Zheng ^a,b,d ,
Xianliang Ke ^a,b ,
Rui Gui ^a,b,d ,
Zhongzi Yao ^a,b,d ,
Jiasong Xiong ^a,b,d ,
Quanjiao Chen ^{a,b,c
,,}

a. CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430207, China;
b. Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430207, China;
c. Hubei Jiangxia Laboratory, Wuhan, 430207, China;
d. University of Chinese Academy of Sciences, Beijing, 100049, China

Corresponding author: Quanjiao Chen, chenqj@wh.iov.cn
Received Date: 14 July 2023
Accepted Date: 10 November 2023
Available online: 13 November 2023

Abstract

Avian H9N2 viruses have wide host range among the influenza A viruses. However, knowledge of H9N2 mammalian adaptation is limited. To explore the molecular basis of the adaptation to mammals, we performed serial lung passaging of the H9N2 strain A/chicken/Hunan/8.27 YYGK3W3-OC/2018 (3W3) in mice and identified six mutations in the hemagglutinin (HA) and polymerase acidic (PA) proteins. Mutations L226Q, T511I, and A528V of HA were responsible for enhanced pathogenicity and viral replication in mice; notably, HA-L226Q was the key determinant. Mutations T97I, I545V, and S594G of PA contributed to enhanced polymerase activity in mammalian cells and increased viral replication levels in vitro and in vivo. PA-T97I increased viral polymerase activity by accelerating the viral polymerase complex assembly. Our findings revealed that the viral replication was affected by the presence of PA-97I and/or PA-545V in combination with a triple-point HA mutation. Furthermore, the double- and triple-point PA mutations demonstrated antagonistic effect on viral replication when combined with HA-226Q. Notably, any combination of PA mutations, along with double-point HA mutations, resulted in antagonistic effect on viral replication. We also observed antagonism in viral replication between PA-545V and PA-97I, as well as between HA-528V and PA-545V. Our findings demonstrated that several antagonistic mutations in HA and PA proteins affect viral replication, which may contribute to the H9N2 virus adaptation to mice and mammalian cells. These findings can potentially contribute to the monitoring of H9N2 field strains for assessing their potential risk in mammals.
- Influenza A virus (IAV)
- , H9N2
- , HA
- , PA
- , Antagonism
- , Mouse adaptation

Electronic Supplementary Material

10.1016j.virs.2023.11.004-ESM.docx
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