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J Biomed Sci. 2020 Jan 6;27(1):17. doi: 10.1186/s12929-019-0612-z.

Genetic variations on 31 and 450 residues of influenza A nucleoprotein affect viral replication and translation.

Author information

1
Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, No.1, University Road, Tainan, 701, Taiwan.
2
National Mosquito-Borne Diseases Control Research Center, National Health Research Institutes, Tainan, Taiwan.
3
Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan.
4
WHO Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, 3000, Australia.
5
Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
6
Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, No.1, University Road, Tainan, 701, Taiwan. jrwang@mail.ncku.edu.tw.
7
Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan. jrwang@mail.ncku.edu.tw.
8
Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan. jrwang@mail.ncku.edu.tw.
9
National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan. jrwang@mail.ncku.edu.tw.

Abstract

BACKGROUND:

Influenza A viruses cause epidemics/severe pandemics that pose a great global health threat. Among eight viral RNA segments, the multiple functions of nucleoprotein (NP) play important roles in viral replication and transcription.

METHODS:

To understand how NP contributes to the virus evolution, we analyzed the NP gene of H3N2 viruses in Taiwan and 14,220 NP sequences collected from Influenza Research Database. The identified genetic variations were further analyzed by mini-genome assay, virus growth assay, viral RNA and protein expression as well as ferret model to analyze their impacts on viral replication properties.

RESULTS:

The NP genetic analysis by Taiwan and global sequences showed similar evolution pattern that the NP backbones changed through time accompanied with specific residue substitutions from 1999 to 2018. Other than the conserved residues, fifteen sporadic substitutions were observed in which the 31R, 377G and 450S showed higher frequency. We found 31R and 450S decreased polymerase activity while the dominant residues (31 K and 450G) had higher activity. The 31 K and 450G showed better viral translation and replication in vitro and in vivo.

CONCLUSIONS:

These findings indicated variations identified in evolution have roles in modulating viral replication in vitro and in vivo. This study demonstrates that the interaction between variations of NP during virus evolution deserves future attention.

KEYWORDS:

Evolution; Ferret study; H3N2; Influenza virus; Nucleoprotein; Viral replication; Viral translation

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