Influenza A Virus Dysregulates Host Histone Deacetylase 1 That Inhibits Viral Infection in Lung Epithelial Cells

Abstract

Viruses dysregulate the host factors that inhibit virus infection. Here, we demonstrate that human enzyme, histone deacetylase 1 (HDAC1) is a new class of host factor that inhibits influenza A virus (IAV) infection, and IAV dysregulates HDAC1 to efficiently replicate in epithelial cells. A time-dependent decrease in HDAC1 polypeptide level was observed in IAV-infected cells, reducing to <50% by 24 h of infection. A further depletion (97%) of HDAC1 expression by RNA interference increased the IAV growth kinetics, increasing it by >3-fold by 24 h and by >6-fold by 48 h of infection. Conversely, overexpression of HDAC1 decreased the IAV infection by >2-fold. Likewise, a time-dependent decrease in HDAC1 activity, albeit with slightly different kinetics to HDAC1 polypeptide reduction, was observed in infected cells. Nevertheless, a further inhibition of deacetylase activity increased IAV infection in a dose-dependent manner. HDAC1 is an important host deacetylase and, in addition to its role as a transcription repressor, HDAC1 has been lately described as a coactivator of type I interferon response. Consistent with this property, we found that inhibition of deacetylase activity either decreased or abolished the phosphorylation of signal transducer and activator of transcription I (STAT1) and expression of interferon-stimulated genes, IFITM3, ISG15, and viperin in IAV-infected cells. Furthermore, the knockdown of HDAC1 expression in infected cells decreased viperin expression by 58% and, conversely, the overexpression of HDAC1 increased it by 55%, indicating that HDAC1 is a component of IAV-induced host type I interferon antiviral response. IMPORTANCEInfluenza A virus (IAV) continues to significantly impact global public health by causing regular seasonal epidemics, occasional pandemics, and zoonotic outbreaks. IAV is among the successful human viral pathogens that has evolved various strategies to evade host defenses, prevent the development of a universal vaccine, and acquire antiviral drug resistance. A comprehensive knowledge of IAV-host interactions is needed to develop a novel and alternative anti-IAV strategy. Host produces a variety of factors that are able to fight IAV infection by employing various mechanisms. However, the full repertoire of anti-IAV host factors and their antiviral mechanisms has yet to be identified. We have identified here a new host factor, histone deacetylase 1 (HDAC1) that inhibits IAV infection. We demonstrate that HDAC1 is a component of host innate antiviral response against IAV, and IAV undermines HDAC1 to limit its role in antiviral response. Influenza A virus (IAV), a prototypic member of family Orthomyxoviridae, has been a successful human respiratory pathogen. IAV has prevented the development of a universal vaccine so far and rendered the currently approved anti-influenza virus drugs almost ineffective. A unique genetic make-up comprising of a segmented RNA genome and a broad host range of humans, birds, pigs, dogs, cats, horses, seals, and bats allows the regular emer...

The Class IV human deacetylase, HDAC11, exhibits anti‐influenza A virus properties via its involvement in host innate antiviral response

“…This indicates that HDAC11 siRNA does contribute to further reducing the HDAC11 mRNA level during the course of infection and, consequently, to IAV proliferation. The extent of increase in virus release from HDAC11‐depleted cells was larger than about 3.0‐, 4.0‐, and 6.0‐fold increase from HDAC 1‐, 2‐, and 6‐depleted cells, respectively, we observed earlier (Husain & Cheung, ; Nagesh et al, ; Nagesh & Husain, ). One of the possible explanations for this could be that, compared with the Classes I and II HDACs, HDAC11 is evolutionarily the least evolved HDAC and has retained the original structure as well as function assigned to its common ancestral gene(s) by nature.…”

“…The data presented above demonstrating the noticeably significant proliferation of IAV in HDAC11‐depleted cells and a profound downregulation of HDAC11 transcript level in infected cells—a sign of viral antagonism of HDAC11—indicated that, like HDAC 1 and 2 (Nagesh et al, ; Nagesh & Husain, ), HDAC11 is part of the host defences. Therefore, we next investigated the role of HDAC11 in IAV‐mediated induction of host IFN response.…”

“…We have identified and characterised a role of multiple human histone deacetylases (HDACs) in IAV infection (Husain & Cheung, ; Nagesh & Husain, ; Nagesh, Hussain, Galvin, & Husain, ). The HDACs are a family of enzymes that were originally described to catalyse the deacetylation of acetylated histones (Seto & Yoshida, ).…”

“…Finally, Class IV possesses a lone member, HDAC11. We have found that members of both the Class I (HDAC 1 and 2) and Class II (HDAC6) possess anti‐IAV properties (Husain & Cheung, ; Nagesh et al, ; Nagesh & Husain, ). Furthermore, all Class III HDACs (SIRT) have been found to exhibit anti‐IAV properties too (Koyuncu et al, ).…”

Multi-Omics Studies towards Novel Modulators of Influenza A Virus–Host Interaction

“…Interestingly, 41 of the 199 druggable cellular factors were shown to be implicated in IAV infection (Table S2) [10,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,...…”