The Interaction Between Class II Histone Deacetylases and the Influenza A Virus-induced Innate Immune Response

Influenza A virus (IAV) remains a significant burden on healthcare systems worldwide and remains a potential pandemic pathogen. Furthermore, the ongoing global spread of highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b poses a nascent threat to our primary industries, native taonga species, and our healthcare system. Therefore, it is critical to identify and characterise the determinants of IAV pathogenesis and disease severity in order to design targeted anti-IAV strategies.It is now clear that acetylation is a proviral host factor, and that histone deacetylases (HDACs) are anti-IAV factors. Recently, HDAC6, a class II HDAC, has been shown to deacetylate retinoic acid-inducible gene I (RIG-I), a pattern recognition receptor (PRR) upon the detection of IAV pathogen-associated molecular patterns (PAMPs). However, it is unclear how HDAC6 affects the signalling pathways downstream of RIG-I. This project investigated the role of class II HDACs, particularly HDAC6, in IAV-induced RIG-I signalling. For this, a cell culture model of IAV infection using human lung epithelial cells, A549 was used. Furthermore, RNA interference was employed to manipulate the expression of HDAC6.Interferon regulatory factor 3 (IRF3) is one of the downstream effectors of RIG-I and is phosphorylated upon IAV infection. Subsequently, IRF3 translocates to the nucleus and induces the expression of interferons (IFNs). Here, we show that HDAC6 is involved in the phosphorylation of IRF3 in response to IAV infection, albeit in a time-dependent manner. Furthermore, we demonstrate that HDAC6 is also involved in the IAV-induced expression of IFNα, IFNβ, and IFNγ over time. We also show that HDAC6 mediates the IAV-induced expression of interferon-stimulated genes (ISGs) in a similar manner.Finally, we show that the expression of class II HDACs, HDACs 4, 5, 6, 7, and 10, are both upregulated and antagonised during IAV infection. However, the expression of class II HDACs, and HDAC6 in particular, are not stimulated by IFNα or IFNβ.These findings help underscore the importance of acetylation in IAV infections and willassist in our understanding of IAV pathogenesis and disease severity.