State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen Universitygrid.12981.33, Guangzhou Higher Education Mega Center, Guangzhou, Guangdong, People's Republic of China.
J Virol. 2022 Jul 27;96(14):e0212721. doi: 10.1128/jvi.02127-21. Epub 2022 Jun 27.
For more than 3 decades, mounting evidence has associated porcine reproductive and respiratory syndrome virus (PRRSV) infection with late-term abortions and stillbirths in sows and respiratory disease in piglets, causing enormous economic losses to the global swine industry. However, to date, the underlying mechanisms of PRRSV-triggered cell death have not been well clarified, especially in the pulmonary inflammatory injury characterized by the massive release of pro-inflammatory factors. Here, we demonstrated that PRRSV infection triggered gasdermin D-mediated host pyroptosis and . Mechanistically, PRRSV infection triggered disassembly of the -Golgi network (TGN); the dispersed TGN then acted as a scaffold for NLRP3 activation through phosphatidylinositol-4-phosphate. In addition, PRRSV replication-transcription complex (RTC) formation stimulated TGN dispersion and pyroptotic cell death. Furthermore, our results indicated that TMEM41B, an endoplasmic reticulum (ER)-resident host protein, functioned as a crucial host factor in the formation of PRRSV RTC, which is surrounded by the intermediate filament network. Collectively, these findings uncover new insights into clinical features as previously unrecognized mechanisms for PRRSV-induced pathological effects, which may be conducive to providing treatment options for PRRSV-associated diseases and may be conserved during infection by other highly pathogenic viruses. Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the pathogens responsible for major economic losses in the global swine industry. Characterizing the detailed process by which PRRSV induces cell death pathways will help us better understand viral pathogenesis and provide implications for therapeutic intervention against PRRSV. Here, we showed that PRRSV infection induces GSDMD-driven host pyroptosis and IL-1β secretion through NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation and . Furthermore, the molecular mechanisms of PRRSV-induced NLRP3 inflammasome activation and pyroptosis are elucidated here. The dispersed -Golgi network (TGN) induced by PRRSV serves as a scaffold for NLRP3 aggregation into multiple puncta via phosphatidylinositol 4-phosphate (PtdIns4P). Moreover, the formation of PRRSV replication-transcription complex is essential for TGN dispersion and host pyroptosis. This research advances our understanding of the PRRSV-mediated inflammatory response and cell death pathways, paving the way for the development of effective treatments for PRRSV diseases.
三十多年来，越来越多的证据表明，猪繁殖与呼吸综合征病毒（PRRSV）感染与母猪晚期流产和死产以及仔猪呼吸道疾病有关，给全球养猪业造成了巨大的经济损失。然而，迄今为止，PRRSV 触发细胞死亡的潜在机制尚不清楚，特别是在以大量释放促炎因子为特征的肺炎症损伤中。在这里，我们证明 PRRSV 感染触发了 gasdermin D 介导的宿主细胞焦亡和 IL-1β 的释放。在机制上，PRRSV 感染触发了高尔基网络（TGN）的解体；分散的 TGN 随后通过磷脂酰肌醇-4-磷酸（PtdIns4P）作为 NLRP3 激活的支架。此外，PRRSV 复制转录复合物（RTC）的形成刺激了 TGN 的分散和细胞焦亡。此外，我们的结果表明，内质网（ER）驻留宿主蛋白 TMEM41B 在 PRRSV RTC 的形成中作为一个关键的宿主因子发挥作用，PRRSV RTC 被中间丝网络包围。总的来说，这些发现揭示了临床特征的新见解，以及以前未被认识到的 PRRSV 诱导病理效应的机制，这可能有助于为 PRRSV 相关疾病提供治疗选择，并可能在其他高致病性病毒感染过程中保守。猪繁殖与呼吸综合征病毒（PRRSV）是导致全球养猪业重大经济损失的病原体之一。阐明 PRRSV 诱导细胞死亡途径的详细过程将有助于我们更好地了解病毒发病机制，并为针对 PRRSV 的治疗干预提供启示。在这里，我们表明 PRRSV 感染通过 NOD、LRR 和 pyrin 结构域包含蛋白 3（NLRP3）炎性小体的激活诱导 GSDMD 驱动的宿主细胞焦亡和 IL-1β 的分泌。此外，这里还阐明了 PRRSV 诱导的 NLRP3 炎性小体激活和细胞焦亡的分子机制。PRRSV 诱导的分散的高尔基网络（TGN）通过磷脂酰肌醇 4-磷酸（PtdIns4P）诱导 NLRP3 聚集形成多个点状结构。此外，PRRSV 复制转录复合物的形成对于 TGN 的分散和宿主细胞焦亡是必不可少的。这项研究推进了我们对 PRRSV 介导的炎症反应和细胞死亡途径的理解，为开发针对 PRRSV 疾病的有效治疗方法铺平了道路。
