The identification of human histone deacetylases, HDAC1 and HDAC2 as novel anti-influenza viral factors Prashanth T. Nagesh1, 2 and Matloob Husain1* 1Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand; 2Department of Microbiology, New York University School of Medicine, New York, USA
Influenza virus is an ever-evolving human pathogen that presents a constant threat to global public and animal health. Therefore, there is an undeniable need to identify the missing links - both host and viral - that are important for influenza virus pathogenesis to develop alternative, effective and long-lasting anti-influenza strategies. We have discovered that human histone deacetylases, HDAC1 and HDAC2 possess anti-influenza properties and are a component of host innate response against influenza. We found that RNA interference-mediated knockdown of HDAC1 and 2 expression augmented the influenza A virus (IAV) growth in A549 cells by more than 3- and 4-fold, respectively. Further, both HDAC1 and 2 exert their anti-IAV function via viperin, an interferon-stimulated gene known to inhibit IAV infection. We found that the expression of viperin was reduced by 58% and 53% in HDAC1- and 2-depleted cells, respectively, in response to IAV infection. However, like other antiviral host factors, influenza antagonizes HDAC1 and 2, and by using the same pathway, to undermine their antiviral function. We found that IAV downregulates the level of HDAC1 and 2, primarily at polypeptide level in A549 cells that can be recovered to almost 100% level in the presence of a proteasome inhibitor. The HDAC1 and 2 are prototypic members of class I HDACs and are closely related in structure and function. Hence, in many heterologous conditions, HDAC1 and 2 behave practically like “twins”. The data generated so far indicate that, in IAV-infected cells, HDAC1 and 2 also behave in a similar fashion. Interestingly, IAV also antagonizes them both in a similar manner. Nevertheless, future investigations will reveal further similarities and differences in anti-influenza viral mechanisms of host HDAC1 and 2.
References: 1) Nagesh PT, Hussain M, Galvin H, Husain M (2017). Histone deacetylase 2 is a component of influenza A virus-induced host antiviral response. Frontiers in Microbiology, 8:1315. 2) Nagesh PT, Husain M (2016). Influenza A virus dysregulates host histone deacetylase 1 that inhibits viral infection in lung epithelial cells. Journal of Virology, 90 (9): 4614-4625.
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