Abstract
Epidemic and pandemic influenza A virus (IAV) poses a significant threat to human populations worldwide. Iridoid glycosides are principal bioactive components from the Gardenia jasminoides J. Ellis fruit that exhibit antiviral activity against several strains of IAV. In the present study, we evaluated the protective effect of Fructus Gardeniae iridoid glycoside extracts (IGEs) against IAV by cytopathogenic effect(CPE), MTT and a plaque formation assay in vitro and examined the reduction in the pulmonary index (PI), restoration of body weight, reduction in mortality and increases in survival time in vivo. As a host factor, PACT provides protection against the pathogenic influenza A virus by interacting with IAV polymerase and activating the IFN-I response. To verify the whether IGEs suppress IAV replication in a PACT-dependent manner, IAV RNA replication, expression of PACT and the phosphorylation of eIF2α in A549 cells were detected; the levels of IFNβ, PACT and PKR in mouse lung tissues were determined; and the activity of IAV polymerase was evaluated in PACT-compromised cells. The results indicated that IGEs sufficiently alleviated cell damage and suppressed IAV replication in vitro, protecting mice from IAV-induced injury and lethal IAV infection. These anti-IAV effects might be related to disrupted interplay between IVA polymerase and PACT and/or prevention of a PACT-dependent overactivated IFN-I antiviral response. Taken together, our findings reveal a new facet of the mechanisms by which IGEs fight the influenza A virus in a PACT-dependent manner.
Highlights
Influenza viruses cause recurrent seasonal epidemics or pandemics of respiratory infection that lead to 3 million to 5 million cases of severe illness and 250,000 to 500,000 deaths worldwide every year[1,2]
PACT is involved in the interaction between influenza A virus (IAV) and host cells, and it can substantially enhance RIG-I activation and phosphorylate eukaryotic translation initiation factor 2 alpha to induce an IFN type I response, which is suppressed by the nonstructural influenza virus protein NS125,26
We first determined the protective effect of the Fructus Gardeniae iridoid glycosides extracts (IGEs) on the cells and mice infected by influenza A virus
Summary
Influenza viruses cause recurrent seasonal epidemics or pandemics of respiratory infection that lead to 3 million to 5 million cases of severe illness and 250,000 to 500,000 deaths worldwide every year[1,2]. It was demonstrated that Fructus Gardeniae iridoid glycoside extracts (IGEs) exhibited antiviral effects against influenza A virus H1N1 and H3N2 subtypes in vitro and in vivo[31]. We first determined the protective effect of the Fructus Gardeniae iridoid glycosides extracts (IGEs) on the cells and mice infected by influenza A virus. We investigated whether the IGEs could inhibit vRNA replication and host factor PACT activation by evaluating the levels of virus replication, protein expression of PACT and phosphorylation of eIF2α in A549 cells and the levels of IFNβ, PACT and PKR in mouse lung tissues. To assess whether IGEs inhibit influenza virus replication in PACT-dependent manner, we measured RNA polymerase activity of influenza virus in HEK-293T cells in which PACT protein expression was knocked down by siRNA
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