12noon Monday 24 June
Room 208, 2nd floor,
Microbiology building
720 Cumberland Street
Mazhar Hussain
University of Otago
The anti-influenza viral mechanism and viral antagonism of host Histone Deacetylase 6
Influenza virus, a prototypic member of the Orthomyxoviridae family, is the causative agent of the respiratory illness “flu”. The World Health Organisation (WHO) estimates ~1 billion cases of flu per year with 3-5 million cases resulting in severe illness including 291,243-645,832 deaths each year. Histone deacetylases (HDACs) are a broad array of enzymes which catalyse the hydrolysis of an N(6)-acetyl-lysine residue of histone or non-histone proteins. HDACs consists of four classes, with HDAC1 and HDAC2 (Class I HDACs), HDAC6 (Class II HDAC) and HDAC11 (Class IV HDAC) showing anti-influenza A virus potential. HDAC6 restricts the release of influenza A virus by deacetylating α−tubulin, and decreasing IAV replication by inhibiting and degrading viral polymerase (PA), and regulating RIG-I dependent innate immune response. During my PhD, I investigated the HDAC6 dependent regulation of innate immune response in influenza A virus (IAV) infected A549 cells. I also investigated the IAV mediated dysregulation of HDAC6 at mRNA and protein level. During IAV infection, HDAC6 regulates the induction of ISGs (IFITM3 and ISG5) by influencing the STAT1 phosphorylation. The small-inhibitor based analysis revealed that deacetylase activity of HDAC6 is required for the regulation of STAT1 phosphorylation. IAV circumvents antiviral potential of HDAC6 by downregulating it at mRNA and polypeptide levels. IAV induces apoptotic proteases, known as caspases, in a lysosome-dependent manner, which cause cleavages in HDAC6. Further analysis revealed that caspase-3 is one of the caspases that cleaves HDAC6
