Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.
Centre for Inflammatory Diseases, Department of Medicine, Monash Medical Centre, Monash University, Monash University, Clayton, VIC, 3168, Australia.
Vet Res. 2022 Jul 29;53(1):61. doi: 10.1186/s13567-022-01077-2.
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 (EC: 0.16-0.20 μM) and may provide opportunities for developing novel anti-PRRSV agents.
猪繁殖与呼吸综合征病毒（PRRSV）是一种流行且地方性的猪病原体，它会给全球养猪业造成重大经济损失。已经开发出多种疫苗来预防 PRRSV 感染。然而，它们提供的保护有限。此外，目前还没有有效的治疗药物。因此，迫切需要开发新的抗病毒策略来预防 PRRSV 感染和传播。在这里，我们报告，川楝素（TSN），一种在川楝或川楝果实中发现的四环三萜，在Marc-145 细胞中和原代猪肺泡巨噬细胞（PAMs）中以亚微米浓度强烈抑制 2 型 PRRSV 的复制。转录组学的结果表明，TSN 上调了 Marc-145 细胞中 IFI16 的表达。此外，我们发现 IFI16 沉默增强了 PRRSV 在 Marc-145 细胞中的复制，而 TSN 的抗 PRRSV 活性被 IFI16 沉默减弱，表明 TSN 抑制 PRRSV 复制是依赖于 IFI16 的。此外，我们表明，TSN 在 IFI16 依赖途径中激活了 caspase-1 并诱导了 IL-1β 的成熟。为了验证 IL-1β 在 PRRSV 感染中的作用，我们分析了外源性 rmIL-1β 对 PRRSV 复制的影响，结果表明，外源性 IL-1β 以剂量依赖的方式显著抑制 Marc-145 细胞和 PAMs 中的 PRRSV 复制。总之，我们的研究结果表明，TSN 在非常低的浓度（EC：0.16-0.20μM）下显著抑制 PRRSV 复制，这可能为开发新型抗 PRRSV 药物提供机会。
