Abstract
The host innate defence against influenza virus infection is an intricate system with a plethora of antiviral factors involved. We have identified host histone deacetylase 6 (HDAC6) as an anti-influenza virus factor in cultured cells. Consistent with this, we report herein that HDAC6 knockout (KO) mice are more susceptible to influenza virus A/PR/8/1934 (H1N1) infection than their wild type (WT) counterparts. The KO mice lost weight faster than the WT mice and, unlike WT mice, could not recover their original body weight. Consequently, more KO mice succumbed to infection, which corresponded with higher lung viral loads. Conversely, the expression of the critical innate antiviral response genes interferon alpha/beta, CD80, CXCL10 and IL15 was significantly downregulated in KO mouse lungs compared to WT mouse lungs. These data are consistent with the known function of HDAC6 of de-acetylating the retinoic acid inducible gene-I (RIG-I) and activating the host innate antiviral response cascade. Loss of HDAC6 thus leads to a blunted innate response and increased susceptibility of mice to influenza A virus infection.
Highlights
Influenza virus continues to be a significant burden and threat to global public health
The histone deacetylase 6 (HDAC6) gene is localised to an X chromosome [16,17] and a knockout (KO) mouse has been created [15]
The genotype of bred mice was determined by PCR and the expression levels of HDAC6 polypeptide, or lack thereof, in mouse lung tissue were confirmed by Western blotting (Figure S1)
Summary
Influenza virus continues to be a significant burden and threat to global public health. Influenza A virus (IAV) is the prototypic and most significant member of Orthomyxoviridae family. IAV possesses a segmented negative-sense, single-stranded RNA genome and exhibits a broad host range. IAV to constantly circulate in nature and generate genetically diverse variants through evolution [1]. These variants cause seasonal epidemics, unpredictable pandemics and zoonotic outbreaks. This evolving nature of IAV has made the development of a universal vaccine difficult and increases the development of resistance against available antiviral drugs [2,3,4]. Considering all IAV characteristics, it is an unlikely candidate for eradication
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