Villamayor Laura, López-García Darío, Rivero Vanessa, Martínez-Sobrido Luis, Nogales Aitor, DeDiego Marta L
Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain.
Texas Biomedical Research Institute, San Antonio, TX, United States.
Front Microbiol. 2023 Apr 28;14:1176177. doi: 10.3389/fmicb.2023.1176177. eCollection 2023.
The recognition of viral nucleic acids by host pattern recognition receptors (PRRs) is critical for initiating innate immune responses against viral infections. These innate immune responses are mediated by the induction of interferons (IFNs), IFN-stimulated genes (ISGs) and pro-inflammatory cytokines. However, regulatory mechanisms are critical to avoid excessive or long-lasting innate immune responses that may cause detrimental hyperinflammation. Here, we identified a novel regulatory function of the ISG, IFN alpha inducible protein 27 (IFI27) in counteracting the innate immune responses triggered by cytoplasmic RNA recognition and binding. Our model systems included three unrelated viral infections caused by Influenza A virus (IAV), Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), and Sendai virus (SeV), and transfection with an analog of double-stranded (ds) RNA. Furthermore, we found that IFI27 has a positive effect on IAV and SARS-CoV-2 replication, most likely due to its ability to counteract host-induced antiviral responses, including . We also show that IFI27 interacts with nucleic acids and PRR retinoic acid-inducible gene I (RIG-I), being the interaction of IFI27 with RIG-I most likely mediated through RNA binding. Interestingly, our results indicate that interaction of IFI27 with RIG-I impairs RIG-I activation, providing a molecular mechanism for the effect of IFI27 on modulating innate immune responses. Our study identifies a molecular mechanism that may explain the effect of IFI27 in counterbalancing innate immune responses to RNA viral infections and preventing excessive innate immune responses. Therefore, this study will have important implications in drug design to control viral infections and viral-induced pathology.
宿主模式识别受体（PRR）对病毒核酸的识别对于启动针对病毒感染的先天性免疫反应至关重要。这些先天性免疫反应由干扰素（IFN）、IFN刺激基因（ISG）和促炎细胞因子的诱导介导。然而，调节机制对于避免可能导致有害的过度炎症的过度或持久的先天性免疫反应至关重要。在这里，我们确定了ISG干扰素α诱导蛋白27（IFI27）在对抗由细胞质RNA识别和结合引发的先天性免疫反应中的一种新的调节功能。我们的模型系统包括由甲型流感病毒（IAV）、严重急性呼吸综合征冠状病毒2（SARS-CoV-2）和仙台病毒（SeV）引起的三种不相关的病毒感染，以及用双链（ds）RNA类似物进行转染。此外，我们发现IFI27对IAV和SARS-CoV-2复制有积极影响，最有可能是由于其抵消宿主诱导的抗病毒反应的能力，包括 。我们还表明IFI27与核酸和PRR视黄酸诱导基因I（RIG-I）相互作用，IFI27与RIG-I的相互作用最有可能通过RNA结合介导。有趣的是，我们的结果表明IFI27与RIG-I的相互作用损害了RIG-I的激活，为IFI27调节先天性免疫反应的作用提供了一种分子机制。我们的研究确定了一种分子机制，该机制可能解释IFI27在平衡对RNA病毒感染的先天性免疫反应和防止过度先天性免疫反应中的作用。因此，这项研究将对控制病毒感染和病毒诱导的病理学的药物设计具有重要意义。
