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Conference Paper: Potential genetic polymorphism of PB2-701 and 702: Implication in virus-host interaction of influenza A virus
Title | Potential genetic polymorphism of PB2-701 and 702: Implication in virus-host interaction of influenza A virus |
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Authors | |
Issue Date | 2017 |
Publisher | International Consortium for Prevention & Infection Control. |
Citation | 4th International Conference on Prevention & Infection Control (ICPIC 2017), Geneva, Switerzland, 20-23 June 2017 How to Cite? |
Abstract | Introduction: PB2-701 of influenza A virus is a genetic marker for host adaptation. A D701N mutation of an avian virus can enhance the polymerase activity and viral replication in mammalian cells. PB2-702 shows host specificity, with most human viruses carry an arginine and most avian viruses carry a lysine. However, limited polymorphisms at these two residues are found in the natural isolates, limiting the study of their role in the polymerase. Objectives: We aim to investigate the potential genetic polymorphism of the PB2-701 and 702 residues by site-directed random mutagenesis of the PB2 gene of the virus. Methods: To elucidate the role of PB2-701/702 in viral fitness, site-directed random mutagenesis of the PB2 gene was performed to generate recombinant viruses with random mutations at PB2-701/702 in mammalian and avian cells. The polymerase activity, viral replication and pathogenicity of the mutant viruses generated were characterized. Results: A wide range of viruses with different PB2-701/702 mutations were isolated. Several mutants demonstrated enhanced polymerase activity in mammalian cells and comparable viral replication and pathogenicity in mice when compared to the wild-type virus. Surface electrostatic charge prediction on the PB2 structural model revealed that the polymerase activity in mammalian cells generally increases as the surface of the PB2-700–703 region becomes more positively charged. On the other hand, some mutants had reduced polymerase activity and viral replication in mammalian cells. One of them (701A/702E) also had lower pathogenicity in mice. Distinct tissue tropism of the PB2-701/702 mutants was observed in chicken embryos. It was found that importin-α4 has a role in the reduction of the polymerase activity in some mutants. Knocking-down the importin-α4 of the mammalian cells enhanced the polymerase activity of the mutants with low polymerase activity, while the importin-α4 inhibitory effect is not significant in other mutants with high polymerase activity. Conclusion: Overall, this study demonstrated the potential genetic polymorphisms at PB2-701/702 and revealed the potential role of importin-α4 in modulating the polymerase activity. The findings in this study may lead to the further study of the role of PB2-701/702 in virus-host interaction and contribute to the control of influenza. |
Description | Poster presentation - Influenza: no. P45 |
Persistent Identifier | http://hdl.handle.net/10722/244592 |
DC Field | Value | Language |
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dc.contributor.author | Chin, WH | - |
dc.contributor.author | Leong, NKC | - |
dc.contributor.author | Poon, LML | - |
dc.date.accessioned | 2017-09-18T01:55:25Z | - |
dc.date.available | 2017-09-18T01:55:25Z | - |
dc.date.issued | 2017 | - |
dc.identifier.citation | 4th International Conference on Prevention & Infection Control (ICPIC 2017), Geneva, Switerzland, 20-23 June 2017 | - |
dc.identifier.uri | http://hdl.handle.net/10722/244592 | - |
dc.description | Poster presentation - Influenza: no. P45 | - |
dc.description.abstract | Introduction: PB2-701 of influenza A virus is a genetic marker for host adaptation. A D701N mutation of an avian virus can enhance the polymerase activity and viral replication in mammalian cells. PB2-702 shows host specificity, with most human viruses carry an arginine and most avian viruses carry a lysine. However, limited polymorphisms at these two residues are found in the natural isolates, limiting the study of their role in the polymerase. Objectives: We aim to investigate the potential genetic polymorphism of the PB2-701 and 702 residues by site-directed random mutagenesis of the PB2 gene of the virus. Methods: To elucidate the role of PB2-701/702 in viral fitness, site-directed random mutagenesis of the PB2 gene was performed to generate recombinant viruses with random mutations at PB2-701/702 in mammalian and avian cells. The polymerase activity, viral replication and pathogenicity of the mutant viruses generated were characterized. Results: A wide range of viruses with different PB2-701/702 mutations were isolated. Several mutants demonstrated enhanced polymerase activity in mammalian cells and comparable viral replication and pathogenicity in mice when compared to the wild-type virus. Surface electrostatic charge prediction on the PB2 structural model revealed that the polymerase activity in mammalian cells generally increases as the surface of the PB2-700–703 region becomes more positively charged. On the other hand, some mutants had reduced polymerase activity and viral replication in mammalian cells. One of them (701A/702E) also had lower pathogenicity in mice. Distinct tissue tropism of the PB2-701/702 mutants was observed in chicken embryos. It was found that importin-α4 has a role in the reduction of the polymerase activity in some mutants. Knocking-down the importin-α4 of the mammalian cells enhanced the polymerase activity of the mutants with low polymerase activity, while the importin-α4 inhibitory effect is not significant in other mutants with high polymerase activity. Conclusion: Overall, this study demonstrated the potential genetic polymorphisms at PB2-701/702 and revealed the potential role of importin-α4 in modulating the polymerase activity. The findings in this study may lead to the further study of the role of PB2-701/702 in virus-host interaction and contribute to the control of influenza. | - |
dc.language | eng | - |
dc.publisher | International Consortium for Prevention & Infection Control. | - |
dc.relation.ispartof | 4th International Conference on Prevention & Infection Control | - |
dc.title | Potential genetic polymorphism of PB2-701 and 702: Implication in virus-host interaction of influenza A virus | - |
dc.type | Conference_Paper | - |
dc.identifier.email | Chin, WH: alexchin@hku.hk | - |
dc.identifier.email | Poon, LML: llmpoon@hkucc.hku.hk | - |
dc.identifier.authority | Chin, WH=rp02345 | - |
dc.identifier.authority | Poon, LML=rp00484 | - |
dc.identifier.hkuros | 276006 | - |