Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Viruses. 2024 Aug 6;16(8):1261. doi: 10.3390/v16081261.
The innate immune system serves as the first line of defense against β-coronaviruses (β-CoVs), a family of viruses that includes SARS-CoV-2. Viral sensing via pattern recognition receptors triggers inflammation and cell death, which are essential components of the innate immune response that facilitate viral clearance. However, excessive activation of the innate immune system and inflammatory cell death can result in uncontrolled release of proinflammatory cytokines, resulting in cytokine storm and pathology. PANoptosis, innate immune, inflammatory cell death initiated by innate immune sensors and driven by caspases and RIPKs through PANoptosome complexes, has been implicated in the pathology of viral infections. Therefore, understanding the molecular mechanisms regulating PANoptosis in response to β-CoV infection is critical for identifying new therapeutic targets that can mitigate disease severity. In the current study, we analyzed findings from a cell death-based CRISPR screen with archetypal β-CoV mouse hepatitis virus (MHV) as the trigger to characterize host molecules required for inflammatory cell death. As a result, we identified SMARCA4, a chromatin regulator, as a putative host factor required for PANoptosis in response to MHV. Furthermore, we observed that gRNA-mediated deletion of inhibited MHV-induced PANoptotic cell death in macrophages. These findings have potential translational and clinical implications for the advancement of treatment strategies for β-CoVs and other infections.
天然免疫系统是抵御β-冠状病毒（β-CoVs）的第一道防线，β-CoVs 是一类病毒，包括 SARS-CoV-2。通过模式识别受体感知病毒会引发炎症和细胞死亡，这是先天免疫反应的重要组成部分，有助于清除病毒。然而，天然免疫系统的过度激活和炎症细胞死亡会导致促炎细胞因子的失控释放，从而引发细胞因子风暴和病理。PANoptosis（由先天免疫传感器引发、通过 PANoptosome 复合物被半胱天冬酶和 RIPKs 驱动的先天免疫驱动的炎症细胞死亡）与病毒感染的病理学有关。因此，了解调节β-CoV 感染后 PANoptosis 的分子机制对于确定可以减轻疾病严重程度的新治疗靶点至关重要。在本研究中，我们分析了基于细胞死亡的 CRISPR 筛选的结果，以典型的β-CoV 小鼠肝炎病毒（MHV）作为触发因素，以表征对炎症细胞死亡至关重要的宿主分子。结果，我们鉴定了染色质调节剂 SMARCA4 是对 MHV 反应中的 PANoptosis 所必需的假定宿主因子。此外，我们观察到 gRNA 介导的缺失抑制了巨噬细胞中 MHV 诱导的 PANoptotic 细胞死亡。这些发现对推进β-CoVs 和其他感染的治疗策略具有潜在的转化和临床意义。
