A Single Amino Acid in the Polymerase Acidic Protein Determines the Pathogenicity of Influenza B Viruses
| Autor: | Sehee Park, Chun Kang, Kisoon Kim, Joon Yong Bae, Ilseob Lee, Joo Yeon Lee, Jin Il Kim, Man Seong Park, Kirim Yoo, Mee Sook Park, Gayeong Kim, Miso Park |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine animal structures Lineage (genetic) viruses Immunology Virulence DNA-Directed DNA Polymerase adaptation Virus Replication medicine.disease_cause Microbiology Virus Mice Viral Proteins 03 medical and health sciences Orthomyxoviridae Infections Virology medicine Influenza A virus Animals pathogenicity Polymerase Mice Inbred BALB C Mutation biology Ferrets influenza B virus Reverse genetics polymerase 030104 developmental biology Viral replication Insect Science embryonic structures biology.protein Pathogenesis and Immunity Female |
| Zdroj: | Journal of Virology |
| ISSN: | 1098-5514 0022-538X |
| Popis: | Influenza B virus (IBV) is one of the human respiratory viruses and one of the targets of seasonal vaccination. However, the bifurcation of two antigenically distinct lineages of IBVs makes it difficult to arrange proper medical countermeasures. Moreover, compared with pathogenicity-related molecular markers known for influenza A virus, little has been known for IBVs. To understand pathogenicity caused by IBVs, we investigated the molecular determinants of IBV pathogenicity in animal models. After serial lung-to-lung passages of Victoria lineage B/Brisbane/60/2008 (Vc_BR60) and Yamagata lineage B/Wisconsin/01/2010 (Ym_WI01) viruses in BALB/c mice, we identified the mouse-adapted Vc_BR60 (maVc_BR60) and Ym_WI01 (maYm_WI01) viruses, respectively. To find a molecular clue(s) to the increased pathogenicity of maVc_BR60 and maYm_WI01, we determined their genetic sequences. Several amino acid mutations were identified in the PB2, PB1, PA, BM2, and/or NS1 protein-coding regions, and one concurrent lysine (K)-to-arginine (R) mutation in PA residue 338 (PA K338R) was found in both maVc_BR60 and maYm_WI01 viruses. When analyzed using viruses rescued through reverse genetics, it was shown that PA K338R alone could increase the pathogenicity of both IBVs in mice and viral replication in the respiratory tracts of ferrets. In a subsequent minireplicon assay, the effect of PA K338R was highlighted by the enhancement of viral polymerase complex activity of both Vc_BR60 and Ym_WI01 viruses. These results suggest that the PA K338R mutation may be a molecular determinant of IBV pathogenicity via modulating the viral polymerase function of IBVs. IMPORTANCE To investigate molecular pathogenic determinants of IBVs, which are one of the targets of seasonal influenza vaccines, we adapted both Victoria and Yamagata lineage IBVs independently in mice. The recovered mouse-adapted viruses exhibited increased virulence, and of the various mutations identified from both mouse-adapted viruses, a concurrent amino acid mutation was found in the PA protein-coding region. When analyzed using viruses rescued through reverse genetics, the PA mutation alone appeared to contribute to viral pathogenicity in mice within the compatible genetic constellation between the IBV lineages and to the replication of IBVs in ferrets. Regarding the potential mechanism of increased viral pathogenicity, it was shown that the PA mutation could upregulate the viral polymerase complex activity of both IBV lineages. These results indicate that the PA mutation could be a newly defined molecular pathogenic determinant of IBVs that substantiates our understanding of the viral pathogenicity and public health risks of IBVs. |
| Databáze: | OpenAIRE |
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