Targeting TRIM28-S473 phosphorylation for the treatment of hyperinflammation during infections with highly pathogenic influenza A viruses and SARS-CoV-2

感染高致病性呼吸道病毒，如H5 N1亚型的甲型流感病毒（HPAIV）和大流行性SARS-CoV-2（COVID-19的病原体），是人类的主要负担。这两种病毒都是通过气溶胶传播的，并导致肺和其他器官的尼古丁驱动的炎症，与促炎细胞因子IL-6、IL-8、TNF-α、CXCL 10和I型IFN的高血液水平相关。诱导这种不平衡的免疫反应的原因仅部分已知。我们证明了宿主因子TRIM 28的磷酸化在HPAIV感染期间的细胞因子风暴诱导中起着至关重要的作用。这通过由PKR/p38/MSK 1构成的信号级联的激活来促进，并导致促炎细胞因子IL-6、IL-8和IFN-β的转录上调。有趣的是，我们发现TRIM 28在SARS-CoV-2感染期间也被磷酸化，并且表明p38 MAPK的抑制导致IL-6、IL-8、TNF-α、CXCL 10和IFN-β的表达减少。这表明在两种病毒感染期间免疫过度诱导的潜在机制相似。该项目旨在通过使用多组学方法在分子水平上揭示TRIM 28介导的免疫应答调节的作用机制。此外，我们希望在我们的临床前人肺外植体模型和患者来源的人肺类器官中探索TRIM 28磷酸化作为COVID-19和HPAIV感染的抗炎治疗的靶标。

Infections with highly pathogenic respiratory viruses such as influenza A viruses of the subtype H5N1 (HPAIV) and the pandemic SARS-CoV-2, the causative agent for COVID-19, are a major burden for human mankind. Both viruses are transmitted by aerosols and result in cytokine-driven inflammation of the lung and other organs, associated with high blood levels of the pro-inflammatory cytokines IL-6, IL-8, TNF-alpha, CXCL10 and the type I IFNs. The reasons for the induction of such unbalanced immune response are only partially known. We demonstrated that phosphorylation of the host factor TRIM28 plays a crucial role in the cytokine storm induction during infection with HPAIV. This is facilitated by activation of a signalling cascade constituted of PKR/p38/MSK1 and results in the transcriptional upregulation of pro-inflammatory cytokines IL-6, IL-8 and IFN-beta. Intriguingly, we discovered that TRIM28 is also phosphorylated during infection with SARS-CoV-2 and showed that inhibition of p38 MAPK leads to reduced expression of IL-6, IL-8, TNF-alpha, CXCL10 and IFN-beta. This suggests similar mechanism underlying immune-hyperinduction during both virus infections. This project aims to unravel the mechanisms of action underlying the TRIM28-mediated regulation of the immune response on a molecular level by using a multiomics approach. Furthermore, we want to explore TRIM28 phosphorylation as a target for anti-inflammatory treatments for COVID-19 and infections with HPAIV in our pre-clinical human lung explant model and patient-derived human lung organoids.