INFLUENZA A VIRUS INFECTION AND UFMYLATION

Abstract

This thesis investigates the interplay between UFMylation, a post-translational modification involving the conjugation of the ubiquitin-like protein Ubiquitin-fold modifier 1 (UFM1) to target proteins, and the replication of Influenza A Virus (IAV) strains PR8 and Udorn. Normally, UFMylation plays different roles in the host cell with main function in proteostasis support via stalled ribosomes degradation and ER-phagy. UFMylation also takes part in immune response and exactly antiviral one via supporting retinoic acid-inducible gene I (RIG-I) pathway activation. It was also already showed that UFMylation can affect Hepatitis A (HAV) replication and can be usurped by Epstein–Barr virus (EBV). Our study provides evidence that UFMylation exerts an antiviral effect against the PR8 strain of IAV, suggesting that the UFMylation pathway plays a crucial role in modulating host defense mechanisms against this virus. Furthermore, we demonstrate that a state of hyper-UFMylation is antiviral specifically against the Udorn strain, indicating that the degree of UFMylation can differentially influence the outcome of infections by distinct strains of IAV. Additionally, our findings reveal that IAV infection can alter the UFMylation status of host proteins, suggesting a complex virus-host interaction where the virus can manipulate host cellular pathways to facilitate its replication. Through the use of UFM1-deficient and hyper-UFMylated cell models, we have dissected the impact of UFMylation on the viral life cycle, providing insights into how modifications in the UFMylation pathway can influence the synthesis of viral proteins and, consequently, viral replication. This research not only expands our understanding of the UFMylation process but also unveils a novel aspect of the molecular battle between IAV and its host. By highlighting the antiviral capabilities of UFMylation and its manipulation by IAV, this thesis lays the groundwork for future investigations into treatment strategies that could affect the UFMylation pathway to fight IAV infections.