Mechanism of action of the suppression of influenza virus replication by Ko-Ken Tang through inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway and viral RNP nuclear export

Ming Sian Wu, Hung Rong Yen, Chia Wen Chang, Tsui Yi Peng, Chung Fan Hsieh, Chi Jene Chen, Tzou Yien Lin, Jim Tong Horng

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Aims of the study: Ko-Ken Tang (KKT, aka kakkon-to), a conventional Chinese herbal medicine, has been used for the treatment of the common cold, fever and influenza virus infection. However, the underlying mechanism of its activity against influenza virus infection remains elusive. In this study, the antiviral effect and its underlying mechanism was evaluated, including the investigation of anti-influenza virus activity of KKT on MDCK cells and corresponding mechanism related to phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and its consecutive viral RNP nuclear export. Materials and methods: The antiviral activity of non-toxic concentration of KKT was examined against various strains of influenza virus and enterovirus 71 by neutralization assay. PI3K/Akt signaling activated by influenza virus was inspected in A549 cells by western blot. Inhibition of influenza polymerase activity by KKT was measured with plasmid-based reverse genetics using primer extension assay and luciferase reporter assay. Inhibition of viral vRNP nuclear export was demonstrated by laser confocal microscopy and interspecies heterokaryon assay. Results: KKT inhibits influenza virus replication but not entry, and it exhibits a broad spectrum inhibitory activity against human influenza A viruses and enterovirus 71. KKT does not inhibit viral polymerase activity but directly blocks the virus-induced phosphatidylinositol 3-kinase/Akt signaling pathway, which in turns causes retention of viral nucleoprotein in the nucleus, thereby interfering with virus propagation. The inhibition by KKT of the nuclear export of viral protein was further confirmed by heterokaryon assay. Conclusions: The results obtained in this study give scientific support to KKT for the treatment of influenza virus infection. KKT could be of potential use in the management of seasonal pandemic influenza virus infection in addition to other clinically available drugs.

Original languageEnglish
Pages (from-to)614-623
Number of pages10
JournalJournal of Ethnopharmacology
Volume134
Issue number3
DOIs
Publication statusPublished - Apr 12 2011
Externally publishedYes

Fingerprint

Phosphatidylinositol 3-Kinase
Cell Nucleus Active Transport
Virus Replication
Orthomyxoviridae
Virus Diseases
Enterovirus
Confocal Microscopy
Human Influenza
Antiviral Agents
Viruses
kamikihi-to
kakkon-to
Reverse Genetics
Rhinovirus
Madin Darby Canine Kidney Cells
Nucleoproteins
Herbal Medicine
Influenza A virus
Viral Proteins
Pandemics

Keywords

  • Cytopathic effect
  • Influenza virus
  • Kakkon-to
  • Ko-Ken Tang
  • Nucleoprotein
  • Phosphatidylinositol 3-kinase/Akt

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

Cite this

Mechanism of action of the suppression of influenza virus replication by Ko-Ken Tang through inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway and viral RNP nuclear export. / Wu, Ming Sian; Yen, Hung Rong; Chang, Chia Wen; Peng, Tsui Yi; Hsieh, Chung Fan; Chen, Chi Jene; Lin, Tzou Yien; Horng, Jim Tong.

In: Journal of Ethnopharmacology, Vol. 134, No. 3, 12.04.2011, p. 614-623.

Research output: Contribution to journalArticle

Wu, Ming Sian ; Yen, Hung Rong ; Chang, Chia Wen ; Peng, Tsui Yi ; Hsieh, Chung Fan ; Chen, Chi Jene ; Lin, Tzou Yien ; Horng, Jim Tong. / Mechanism of action of the suppression of influenza virus replication by Ko-Ken Tang through inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway and viral RNP nuclear export. In: Journal of Ethnopharmacology. 2011 ; Vol. 134, No. 3. pp. 614-623.
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abstract = "Aims of the study: Ko-Ken Tang (KKT, aka kakkon-to), a conventional Chinese herbal medicine, has been used for the treatment of the common cold, fever and influenza virus infection. However, the underlying mechanism of its activity against influenza virus infection remains elusive. In this study, the antiviral effect and its underlying mechanism was evaluated, including the investigation of anti-influenza virus activity of KKT on MDCK cells and corresponding mechanism related to phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and its consecutive viral RNP nuclear export. Materials and methods: The antiviral activity of non-toxic concentration of KKT was examined against various strains of influenza virus and enterovirus 71 by neutralization assay. PI3K/Akt signaling activated by influenza virus was inspected in A549 cells by western blot. Inhibition of influenza polymerase activity by KKT was measured with plasmid-based reverse genetics using primer extension assay and luciferase reporter assay. Inhibition of viral vRNP nuclear export was demonstrated by laser confocal microscopy and interspecies heterokaryon assay. Results: KKT inhibits influenza virus replication but not entry, and it exhibits a broad spectrum inhibitory activity against human influenza A viruses and enterovirus 71. KKT does not inhibit viral polymerase activity but directly blocks the virus-induced phosphatidylinositol 3-kinase/Akt signaling pathway, which in turns causes retention of viral nucleoprotein in the nucleus, thereby interfering with virus propagation. The inhibition by KKT of the nuclear export of viral protein was further confirmed by heterokaryon assay. Conclusions: The results obtained in this study give scientific support to KKT for the treatment of influenza virus infection. KKT could be of potential use in the management of seasonal pandemic influenza virus infection in addition to other clinically available drugs.",
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AU - Yen, Hung Rong

AU - Chang, Chia Wen

AU - Peng, Tsui Yi

AU - Hsieh, Chung Fan

AU - Chen, Chi Jene

AU - Lin, Tzou Yien

AU - Horng, Jim Tong

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N2 - Aims of the study: Ko-Ken Tang (KKT, aka kakkon-to), a conventional Chinese herbal medicine, has been used for the treatment of the common cold, fever and influenza virus infection. However, the underlying mechanism of its activity against influenza virus infection remains elusive. In this study, the antiviral effect and its underlying mechanism was evaluated, including the investigation of anti-influenza virus activity of KKT on MDCK cells and corresponding mechanism related to phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and its consecutive viral RNP nuclear export. Materials and methods: The antiviral activity of non-toxic concentration of KKT was examined against various strains of influenza virus and enterovirus 71 by neutralization assay. PI3K/Akt signaling activated by influenza virus was inspected in A549 cells by western blot. Inhibition of influenza polymerase activity by KKT was measured with plasmid-based reverse genetics using primer extension assay and luciferase reporter assay. Inhibition of viral vRNP nuclear export was demonstrated by laser confocal microscopy and interspecies heterokaryon assay. Results: KKT inhibits influenza virus replication but not entry, and it exhibits a broad spectrum inhibitory activity against human influenza A viruses and enterovirus 71. KKT does not inhibit viral polymerase activity but directly blocks the virus-induced phosphatidylinositol 3-kinase/Akt signaling pathway, which in turns causes retention of viral nucleoprotein in the nucleus, thereby interfering with virus propagation. The inhibition by KKT of the nuclear export of viral protein was further confirmed by heterokaryon assay. Conclusions: The results obtained in this study give scientific support to KKT for the treatment of influenza virus infection. KKT could be of potential use in the management of seasonal pandemic influenza virus infection in addition to other clinically available drugs.

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