Amino Acid Mutations PB1-V719M and PA-N444D Combined with PB2-627K Contribute to the Pathogenicity of H7N9 in Mice

Overview

Journal Vet Res

Publisher Biomed Central

Specialty Veterinary Medicine

Date 2024 Jul 5

PMID 38970119

Authors

Xiaoquan Wang

Xin-En Tang

Huafen Zheng

Ruyi Gao

Xiaolong Lu

Wenhao Yang

Le Zhou

Yu Chen

Min Gu

Jiao Hu

Xiaowen Liu

Shunlin Hu

Kaituo Liu

Xiufan Liu

Affiliations

Soon will be listed here.

Abstract

H7N9 subtype avian influenza viruses (AIVs) cause 1567 human infections and have high mortality, posing a significant threat to public health. Previously, we reported that two avian-derived H7N9 isolates (A/chicken/Eastern China/JTC4/2013 and A/chicken/Eastern China/JTC11/2013) exhibit different pathogenicities in mice. To understand the genetic basis for the differences in virulence, we constructed a series of mutant viruses based on reverse genetics. We found that the PB2-E627K mutation alone was not sufficient to increase the virulence of H7N9 in mice, despite its ability to enhance polymerase activity in mammalian cells. However, combinations with PB1-V719M and/or PA-N444D mutations significantly enhanced H7N9 virulence. Additionally, these combined mutations augmented polymerase activity, thereby intensifying virus replication, inflammatory cytokine expression, and lung injury, ultimately increasing pathogenicity in mice. Overall, this study revealed that virulence in H7N9 is a polygenic trait and identified novel virulence-related residues (PB2-627K combined with PB1-719M and/or PA-444D) in viral ribonucleoprotein (vRNP) complexes. These findings provide new insights into the molecular mechanisms underlying AIV pathogenesis in mammals, with implications for pandemic preparedness and intervention strategies.

References

Qi X, Qiu H, Hao S, Zhu F, Huang Y, Xu K . Human Infection with an Avian-Origin Influenza A (H10N3) Virus. N Engl J Med. 2022; 386(11):1087-1088. DOI: 10.1056/NEJMc2112416. View

Taubenberger J, Reid A, Lourens R, Wang R, Jin G, Fanning T . Characterization of the 1918 influenza virus polymerase genes. Nature. 2005; 437(7060):889-93. DOI: 10.1038/nature04230. View

Wandzik J, Kouba T, Karuppasamy M, Pflug A, Drncova P, Provaznik J . A Structure-Based Model for the Complete Transcription Cycle of Influenza Polymerase. Cell. 2020; 181(4):877-893.e21. DOI: 10.1016/j.cell.2020.03.061. View

Zhang X, Li Y, Jin S, Zhang Y, Sun L, Hu X . PB1 S524G mutation of wild bird-origin H3N8 influenza A virus enhances virulence and fitness for transmission in mammals. Emerg Microbes Infect. 2021; 10(1):1038-1051. PMC: 8183522. DOI: 10.1080/22221751.2021.1912644. View

Wang D, Zhu W, Yang L, Shu Y . The Epidemiology, Virology, and Pathogenicity of Human Infections with Avian Influenza Viruses. Cold Spring Harb Perspect Med. 2020; 11(4). PMC: 8015695. DOI: 10.1101/cshperspect.a038620. View

Shu Y, McCauley J . GISAID: Global initiative on sharing all influenza data - from vision to reality. Euro Surveill. 2017; 22(13). PMC: 5388101. DOI: 10.2807/1560-7917.ES.2017.22.13.30494. View

Ma S, Zhang B, Shi J, Yin X, Wang G, Cui P . Amino Acid Mutations A286V and T437M in the Nucleoprotein Attenuate H7N9 Viruses in Mice. J Virol. 2019; 94(2). PMC: 6955278. DOI: 10.1128/JVI.01530-19. View

Li K, Guan Y, Wang J, Smith G, Xu K, Duan L . Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature. 2004; 430(6996):209-13. DOI: 10.1038/nature02746. View

Subbarao E, LONDON W, Murphy B . A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J Virol. 1993; 67(4):1761-4. PMC: 240216. DOI: 10.1128/JVI.67.4.1761-1764.1993. View

10.

Zhu W, Feng Z, Chen Y, Yang L, Liu J, Li X . Mammalian-adaptive mutation NP-Q357K in Eurasian H1N1 Swine Influenza viruses determines the virulence phenotype in mice. Emerg Microbes Infect. 2019; 8(1):989-999. PMC: 6609330. DOI: 10.1080/22221751.2019.1635873. View

11.

Liu W, Li J, Zou R, Pan J, Jin T, Li L . Dynamic PB2-E627K substitution of influenza H7N9 virus indicates the in vivo genetic tuning and rapid host adaptation. Proc Natl Acad Sci U S A. 2020; 117(38):23807-23814. PMC: 7519270. DOI: 10.1073/pnas.2013267117. View

12.

Eccles R . Why is temperature sensitivity important for the success of common respiratory viruses?. Rev Med Virol. 2020; 31(1):1-8. PMC: 7435572. DOI: 10.1002/rmv.2153. View

13.

Liu K, Ding P, Pei Y, Gao R, Han W, Zheng H . Emergence of a novel reassortant avian influenza virus (H10N3) in Eastern China with high pathogenicity and respiratory droplet transmissibility to mammals. Sci China Life Sci. 2021; 65(5):1024-1035. DOI: 10.1007/s11427-020-1981-5. View

14.

Zhou Y, Wu X, Yan D, Chen C, Liu X, Huang C . V292I mutation in PB2 polymerase induces increased effects of E627K on influenza H7N9 virus replication in cells. Virus Res. 2020; 291:198186. DOI: 10.1016/j.virusres.2020.198186. View

15.

Liang L, Jiang L, Li J, Zhao Q, Wang J, He X . Low Polymerase Activity Attributed to PA Drives the Acquisition of the PB2 E627K Mutation of H7N9 Avian Influenza Virus in Mammals. mBio. 2019; 10(3). PMC: 6581862. DOI: 10.1128/mBio.01162-19. View

16.

Chen Y, Liang W, Yang S, Wu N, Gao H, Sheng J . Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet. 2013; 381(9881):1916-25. PMC: 7134567. DOI: 10.1016/S0140-6736(13)60903-4. View

17.

Resa-Infante P, Bonet J, Thiele S, Alawi M, Stanelle-Bertram S, Tuku B . Alternative interaction sites in the influenza A virus nucleoprotein mediate viral escape from the importin-α7 mediated nuclear import pathway. FEBS J. 2019; 286(17):3374-3388. DOI: 10.1111/febs.14868. View

18.

Yamayoshi S, Yamada S, Fukuyama S, Murakami S, Zhao D, Uraki R . Virulence-affecting amino acid changes in the PA protein of H7N9 influenza A viruses. J Virol. 2013; 88(6):3127-34. PMC: 3957961. DOI: 10.1128/JVI.03155-13. View

19.

Kong H, Ma S, Wang J, Gu C, Wang Z, Shi J . Identification of Key Amino Acids in the PB2 and M1 Proteins of H7N9 Influenza Virus That Affect Its Transmission in Guinea Pigs. J Virol. 2019; 94(1). PMC: 6912098. DOI: 10.1128/JVI.01180-19. View

20.

Wang X, Zheng H, Gao R, Ren L, Jin M, Ji Z . Genetically Related Avian Influenza H7N9 Viruses Exhibit Different Pathogenicity in Mice. Animals (Basel). 2023; 13(23). PMC: 10705590. DOI: 10.3390/ani13233680. View