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.
Highlights
Influenza viruses are negative-sense RNA viruses of the family Orthomyxoviridae [1], and are classified into 3 serotypes, namely A, B, and C
Among the plant extracts tested during preliminary experiments, we found that 30% EtOH extract of ivy leaf showed significant antiviral activity when combined with oseltamivir in vitro
We created a mouse model that reflects the clinical situation of influenza virus infection; we administered suboptimal doses of oral oseltamivir to mice 2 days after infection with a sublethal dose of PR8 virus
Summary
Influenza viruses are negative-sense RNA viruses of the family Orthomyxoviridae [1], and are classified into 3 serotypes, namely A, B, and C. Influenza viruses resistant to M2 inhibitors are widespread and limit the efficacy of anti-influenza drugs. Oseltamivir, zanamivir, and peramivir are potent and selective inhibitors of neuraminidase proteins found in influenza A and B viruses that were recently introduced to treat infected patients [5,6]. Neuraminidase inhibitors effectively limit influenza virus infection by inhibiting the cleavage of sialic acid residues on newly formed virions, thereby blocking the release and spread of progeny virions [7]. The recent emergence of oseltamivir-resistant influenza virus variants aroused concern about a potential pandemic outbreak [8]. The emergence of influenza virus resistant to neuraminidase inhibitors is a matter of great concern, and developing novel antiinfluenza drugs with mechanisms of actions independent of neuraminidase should be urgently addressed [11]
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