Project Details
Abstract
Influenza A viruses are rapidly transmitted from humans to humans and cause widespread epidemics, and the virulent strains of influenza A viruses are responsible for high-mortality pandemics. The virus specific RNA synthesis is catalyzed by the influenza A virus RNA polymerase. The polymerase functions as a transcriptase for viral messenger RNA synthesis using a capped RNA as a primer, and it is also a replicase for virion RNA (vRNA) synthesis without a primer in presence of viral nucleocapsid protein (NP). This polymerase is comprised of three subunits, PB1, PB2 and PA, and the PA subunit contains an intrinsic endonuclease activity which is required for excising capped RNA primer from host cells.
According our preliminary studies, the polymerase complex of highly pathogenic strain, A/HK/483/97/H5N1 (HK483), possesses higher activity than the polymerase complex from A/Udorn/1972/H3N2 (Ud) strain. We have also found that the N’-terminal domain of PA protein may contain the determinants for the increased polymerase activity of the highly pathogenic influenza viruses. Since influenza polymerase catalyzes the virus genome and mRNA synthesis, the high efficiency of the polymerase has been considered as a significant virulence determinant for the virus infection in humans. The presence of those residues may be an indicator for virus pathogenicity. Therefore, we intend to determine the residues on the N’-terminal region of PA subunit that can enhance the activity of influenza polymerase. We will also establish an in vitro reconstitution system with purified polymerase complexes and a synthetic vRNA template to elucidate the mechanisms that may be involved in the enhanced activity. Because several evidences have implicated that host or viral factors, including influenza nonstructural protein 1 (NS1), participate in influenza virus RNA synthesis, one of our goals in this grant proposal is to identify the specific host or viral proteins that interact with the specific influenza polymerase complex. In addition, we intend to reveal the roles of the identified proteins and the NS1 protein in viral RNA synthesis by the established in vitro assays and by virus infection. The information from this study should facilitate the development of anti-viral drugs in the future.
Project IDs
Project ID:PC10101-2089
External Project ID:NSC100-2320-B182-019-MY3
External Project ID:NSC100-2320-B182-019-MY3
Status | Finished |
---|---|
Effective start/end date | 01/08/12 → 31/07/13 |
Keywords
- Influenza A virus
- RNA polymerase
- PA subunit
- AIFM1
- ANT2
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