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The amino acid mutations A286V and T437M in the nucleoprotein attenuate H7N9 viruses in mice

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  • The amino acid mutations A286V and T437M in the nucleoprotein attenuate H7N9 viruses in mice


    J Virol. 2019 Oct 30. pii: JVI.01530-19. doi: 10.1128/JVI.01530-19. [Epub ahead of print] The amino acid mutations A286V and T437M in the nucleoprotein attenuate H7N9 viruses in mice.

    Ma S1, Zhang B1, Shi J1, Yin X1, Wang G1, Cui P1, Liu L1, Deng G1, Jiang Y1, Li C1, Chen H2.
    Author information

    1 State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, CAAS, People's Republic of China. 2 State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, CAAS, People's Republic of China. chenhualan@caas.cn.

    Abstract

    The low pathogenic H7N9 influenza viruses that emerged in 2013 acquired an insertion of four amino acids in their hemagglutinin cleavage site and thereby became highly pathogenic to chickens in 2017. Previous studies indicate that these highly pathogenic H7N9 viruses are virulent in chickens but have distinct pathotypes in mice. A/chicken/Guangdong/SD098 (CK/SD098) is avirulent with a mouse lethal dose (MLD50) greater than 7.5 log10 50% egg infectious dose (EID50), whereas A/chicken/Hunan/S1220 (CK/S1220) is virulent in mice with an MLD50 of 3.2 log10 EID50 In this study, we explored the genetic determinants that contribute to the difference in virulence between these two H7N9 viruses by generating a series of reassortants and mutants in the CK/S1220 virus background and testing their virulence in mice. We found that the reassortant CK/1220-SD098-NP carrying the nucleoprotein (NP) of CK/SD098 was avirulent in mice, with an MLD50 greater than 107.5 EID50 The NP proteins of these two viruses differ by two amino acids at positions 286 and 437. We further demonstrated that the two amino acid mutations A286V and T437M of NP independently slow down the process of NP import to and export from the nucleus, and thus jointly impaired the viral life cycle and attenuated the virulence of these H7N9 viruses in mice. Our study identified new virulence determinants in NP and provided novel targets for the development of live attenuated vaccine and antiviral drugs against influenza viruses.Importance The H7N9 influenza viruses that emerged in China in 2013 have caused over 1,500 human infections, with a mortality of nearly 40%. The viruses were initially low pathogenic but became highly pathogenic in chickens at the beginning of 2017 and caused severe disease outbreaks in poultry. Several studies suggest that the highly pathogenic H7N9 viruses have increased virulence in mammals; however, the genetic basis of the virulence of H7N9 viruses in mammals is not fully understood. Here, we found that two amino acids, 286A and 437T, in NP are prerequisites for the virulence of H7N9 viruses in mice, and that the mutations A286V and T437M collectively eliminate the virulence of H7N9 viruses in mice. Our study further demonstrated that the virulence of influenza virus is polygenic trait, and the newly identified virulence-related residues in NP may provide new targets for attenuated influenza vaccine and antiviral drug development.
    Copyright ? 2019 Ma et al.


    PMID: 31666373 DOI: 10.1128/JVI.01530-19
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