The Mechanism Of Histone Deacetylase Inhibitors In Inhibiting Pseudorabies Virus Infection

Histone deacetylases(HDACs)regulates the structure of histone and chromatin through deacetylation to affect gene transcription,cell proliferation,differentiation,and normal organ growth and development.Virus relies on histone acetylases and deacetylases to regulate histone structure and thereby regulate their gene expression.However,there is no report on the relationship between Pseudorabies virus(PRV)replication and histone deacetylation.Based on this,firstly,this experiment treated PK15 cells with HDAC1 inhibitor TSA and infected PRV to explore the effect of HDAC1 on the proliferation of PRV.The results of the experiment found that TSA inhibited PRV infection.Further using RNAi to interfere with the expression of HDAC1,that was found it also inhibited PRV infection,while overexpression of HDAC1 promoted PRV infection,indicating that HD AC1 is closely related to PRV infection.In order to explore how HDAC1 inhibition affects PRV infection,this experiment first tested the effect of TSA on PRV gene transcription.The results of qRT-PCR showed that TSA significantly inhibited the transcription of PRV IE 180,UL5,UL9,EP0 and US1 genes.Secondly,this test detects the activation of antiviral innate immunity.The test results show that TSA significantly activates the expression of inflammatory cytokines such as IFN-β and IL-1β.Using immunofluorescence and comet experiments,it has been found that TSA can induce DNA damage,and the damaged DNA enters the cytoplasm and combines with cGAS.Further use of CRISPR/Cas9 genome editing technology to knock out the expression of cGAS,STING,TBK1 and IRF3 inhibits the expression of TSA-induced IFN-β and its downstream ISG15,suggesting that inhibition of HDAC1 activates the cGAS-STING natural immune signal pathway and the interferon signal pathway.In summary,inhibiting HDAC1 can induce DNA damage,which in turn activates the cGAS-STING innate immune signaling pathway and the interferon signaling pathway,thereby inhibiting PRV replication.These research results reveal the specific molecular mechanism by which HDAC1 inhibits PRV infection and provide a new theoretical basis for the prevention and control of PRV.