Coadministration of Hedera helix L. Extract Enabled Mice to Overcome Insufficient Protection against Influenza A/PR/8 Virus Infection under Suboptimal Treatment with Oseltamivir

PLoS One. 2015 Jun 22;10(6):e0131089. doi: 10.1371/journal.pone.0131089. eCollection 2015.

Abstract

Several anti-influenza drugs that reduce disease manifestation exist, and although these drugs provide clinical benefits in infected patients, their efficacy is limited by the emergence of drug-resistant influenza viruses. In the current study, we assessed the therapeutic strategy of enhancing the antiviral efficacy of an existing neuraminidase inhibitor, oseltamivir, by coadministering with the leaf extract from Hedera helix L, commonly known as ivy. Ivy extract has anti-inflammatory, antibacterial, antifungal, and antihelminthic properties. In the present study, we investigated its potential antiviral properties against influenza A/PR/8 (PR8) virus in a mouse model with suboptimal oseltamivir that mimics a poor clinical response to antiviral drug treatment. Suboptimal oseltamivir resulted in insufficient protection against PR8 infection. Oral administration of ivy extract with suboptimal oseltamivir increased the antiviral activity of oseltamivir. Ivy extract and its compounds, particularly hedrasaponin F, significantly reduced the cytopathic effect in PR8-infected A549 cells in the presence of oseltamivir. Compared with oseltamivir treatment alone, coadministration of the fraction of ivy extract that contained the highest proportion of hedrasaponin F with oseltamivir decreased pulmonary inflammation in PR8-infected mice. Inflammatory cytokines and chemokines, including tumor necrosis factor-alpha and chemokine (C-C motif) ligand 2, were reduced by treatment with oseltamivir and the fraction of ivy extract. Analysis of inflammatory cell infiltration in the bronchial alveolar of PR8-infected mice revealed that CD11b+Ly6G+ and CD11b+Ly6Cint cells were recruited after virus infection; coadministration of the ivy extract fraction with oseltamivir reduced infiltration of these inflammatory cells. In a model of suboptimal oseltamivir treatment, coadministration of ivy extract fraction that includes hedrasaponin F increased protection against PR8 infection that could be explained by its antiviral and anti-inflammatory activities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / administration & dosage*
  • Bronchoalveolar Lavage Fluid / cytology
  • Bronchoalveolar Lavage Fluid / immunology
  • Cytokines / metabolism
  • Cytopathogenic Effect, Viral / drug effects
  • Drug Synergism
  • Drug Therapy, Combination
  • Enzyme Inhibitors / administration & dosage
  • Hedera*
  • In Vitro Techniques
  • Inflammation / drug therapy
  • Inflammation / immunology
  • Inflammation / pathology
  • Influenza A virus / drug effects*
  • Influenza A virus / pathogenicity
  • Lung / drug effects
  • Lung / immunology
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Neuraminidase / antagonists & inhibitors
  • Orthomyxoviridae Infections / drug therapy*
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / virology
  • Oseltamivir / administration & dosage*
  • Phytotherapy*
  • Plant Extracts / administration & dosage
  • Saponins / administration & dosage

Substances

  • Antiviral Agents
  • Cytokines
  • Enzyme Inhibitors
  • Plant Extracts
  • Saponins
  • Oseltamivir
  • Neuraminidase

Grants and funding

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and future Planning (NRF- 428 2014R1A2A2A01002576). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. HGJ and JGK are employed by Ahngook pharm. Ahngook pharm. provided support in the form of salaries for authors HGJ and JGK and provided hederasaponin F, after isolating and identifying the structure of hederasaponin F, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.