Porcine reproductive and respiratory syndrome virus (PRRSV) is a continuous threat to the pork industry as it continues to cause significant economic loss worldwide. Currently, vaccination strategies provide very limited protection against PRRSV transmission. Consequently, there is an urgent need to develop new antiviral strategies. Platycodin D (PD) is one of the major bioactive triterpenoid saponins derived from Platycodon grandiflorum, a traditional Chinese medicine used as an expectorant for pulmonary diseases and a remedy for respiratory disorders. Here, we demonstrate that PD exhibits potent activity against PRRSV infection in Marc-145 cells and primary porcine alveolar macrophages. PD exhibited broad-spectrum inhibitory activities in vitro against high pathogenic type 2 PRRSV GD-HD strain and GD-XH strain as well as classical CH-1a and VR2332 strains. PD at concentrations ranging 1–4 μM significantly inhibited PRRSV RNA synthesis, viral protein expression and progeny virus production in a dose-dependent manner. EC50 values of PD against four tested PRRSV strains infection in Marc-145 cells ranged from 0.74 to 1.76 μM. Mechanistically, PD inhibited PRRSV replication by directly interacting with virions therefore affecting multiple stages of the virus life cycle, including viral entry and progeny virus release. In addition, PD decreased PRRSV- and LPS-induced cytokine (IFN-α, IFN-β, IL-1α, IL-6, IL-8 and TNF-α) production in PAMs. Altogether, our findings suggested that PD is a potent inhibitor of PPRSV infection in vitro. However, further in vivo studies are necessary to confirm PD as a potential novel and effective PPRSV inhibitor in swine.
Porcine Reproductive and Respiratory Syndrome virus (PRRSV) causes significant economic losses to the pork industry worldwide. Currently, vaccine strategies provide limited protection against PRRSV transmission, and no effective drug is commercially available. Therefore, there is an urgent need to develop novel antiviral strategies to prevent PRRSV pandemics. This study showed that artesunate (AS), one of the antimalarial drugs, potently suppressed PRRSV replication in Marc-145 cells and ex vivo primary porcine alveolar macrophages (PAMs) at micromolar concentrations. Furthermore, we demonstrated that this suppression was closely associated with AS-activated AMPK (energy homeostasis) and Nrf2/HO-1 (inflammation) signaling pathways. AS treatment promoted p-AMPK, Nrf2 and HO-1 expression, and thus inhibited PRRSV replication in Marc-145 and PAM cells in a time- and dose-dependent manner. These effects of AS were reversed when AMPK or HO-1 gene was silenced by siRNA. In addition, we demonstrated that AMPK works upstream of Nrf2/HO-1 as its activation by AS is AMPK-dependent. Adenosine phosphate analysis showed that AS activates AMPK via improving AMP/ADP:ATP ratio rather than direct interaction with AMPK. Altogether, our findings indicate that AS could be a promising novel therapeutics for controlling PRRSV and that its anti-PRRSV mechanism, which involves the functional link between energy homeostasis and inflammation suppression pathways, may provide opportunities for developing novel antiviral agents. Importance Porcine reproductive and respiratory syndrome virus (PRRSV) infections have been continuously threatened the pork industry worldwide. Vaccination strategies provide very limited protection against PRRSV infection, and no effective drug is commercially available. We show that artesunate (AS), one of the antimalarial drugs, is a potent inhibitor against PRRSV replication in Marc-145 cells and ex vivo primary porcine alveolar macrophages (PAMs). Furthermore, we demonstrate that AS inhibits PRRSV replication via activation of AMPK-dependent Nrf2/HO-1 signaling pathways, revealing a novel link between energy homeostasis (AMPK) and inflammation suppression (Nrf2/HO-1) during viral infection. Therefore, we believe that AS may be a promising novel therapeutics for controlling PRRSV, and its anti-PRRSV mechanism may provide a potential strategy to develop novel antiviral agents.
Porcine reproductive and respiratory syndrome virus (PRRSV) is a prevalent and endemic swine pathogen which causes significant economic losses in the global swine industry. Multiple vaccines have been developed to prevent PRRSV infection. However, they provide limited protection. Moreover, no effective therapeutic drugs are yet available. Therefore, there is an urgent need to develop novel antiviral strategies to prevent PRRSV infection and transmission. Here we report that Toosendanin (TSN), a tetracyclic triterpene found in the bark or fruits of Melia toosendan Sieb. et Zucc., strongly suppressed type 2 PRRSV replication in vitro in Marc-145 cells and ex vivo in primary porcine alveolar macrophages (PAMs) at sub-micromolar concentrations. The results of transcriptomics revealed that TSN up-regulated the expression of IFI16 in Marc-145 cells. Furthermore, we found that IFI16 silencing enhanced the replication of PRRSV in Marc-145 cells and that the anti-PRRSV activity of TSN was dampened by IFI16 silencing, suggesting that the inhibition of TSN against PRRSV replication is IFI16-dependent. In addition, we showed that TSN activated caspase-1 and induced maturation of IL-1β in an IFI16-dependent pathway. To verify the role of IL-1β in PRRSV infection, we analyzed the effect of exogenous rmIL-1β on PRRSV replication, and the results showed that exogenous IL-1β significantly inhibited PRRSV replication in Marc-145 cells and PAMs in a dose-dependent manner. Altogether, our findings indicate that TSN significantly inhibits PRRSV replication at very low concentrations (EC50: 0.16–0.20 μM) and may provide opportunities for developing novel anti-PRRSV agents.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.