Abstract
Virus-host interactions are crucial for understanding viral pathogenesis, identifying potential targets for antiviral therapies, and developing prevention strategies. It involves investigating viral replication mechanisms, host responses to infection, and virus-host interactions. Influenza A virus (IAV) is a highly contagious respiratory pathogen that causes seasonal influenza outbreaks and irregular pandemics. IAV undergoes frequent genetic changes through antigenic drift and intermittent antigenic shift. These changes pose challenges for vaccine development and necessitate annual updates to maintain efficacy against evolving strains.
IAV exhibits intricate interactions with its host, leading to the establishment and progression of infection. Upon infection, the virus manipulates host cellular machinery to replicate its genetic material and produce viral proteins. This often triggers an immune response, involving both innate and adaptive components. The virus can modulate host immune responses to its advantage, dampening antiviral defences while promoting an inflammatory environment. One of these host proteins with which IAV interacts is histone deacetylase (HDAC).
This thesis discusses the anti-IAV regulatory role of HDAC5, 6, 7, 9 and 10. During IAV infection, HDACs regulate host innate immune signaling. Our study shows that HDAC5, 6, 7, 9 and 10 also play a crucial role in fighting IAV. First, we show HDAC10 is an anti-IAV factor involved in JAK-STAT pathway regulation. Ultimately, HDAC10 regulates downstream interferon-stimulated genes (ISGs) by interfering with type 1 and type 2 interferon signaling. Consequently, the virus antagonizes HDAC10 at the mRNA and polypeptide levels. We then explored the global effectors of HDAC6 in IAV-mediated immune responses. Transcriptomic screening revealed a whole new set of host proteins that could be utilized as antiviral targets. Towards the end, we show that HDAC5, 7 and 9 (rest of class II HDACs; rocIIH) play an antiviral role during IAV. Furthermore, rocIIH regulates interferon signaling, STAT phosphorylation and ISG transcription. Finally, we demonstrate the antagonistic action of IAV on HDAC5, 7 and 9 as well as the newly established genetic compensation between class II HDACs. Virus-host interactions are dynamic and multifaceted processes that shape the outcomes of viral infections. This interaction between IAV and HDACs represents an intriguing avenue for understanding viral pathogenesis and developing novel antiviral strategies.