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

• Applicant: Dr. Linda Brunotte
• Subject Area: Virology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 503948184

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.

• DFG Programme: Research Grants
• International Connection: USA
• Cooperation Partner: Professor Ivan D' Orso, Ph.D.