Mechanism Of HSV-1 Envelope Protein GL Escaped Host Innate Immune Response And Mediated Host Injury

Herpes simplex virus 1(HSV-1) is a member of the Herpesviridae family of Herpesviridae,which is a neurotropic pathogen widespread in human population.It often causes maternal abortion,fetal malformation,infectious mononucleosis,encephalitis,tumor and additional Alzheimer's disease.The diameter of virus is approximately 225 nm,and the center is a large linear double-stranded DNA(ds DNA)genome(152 kbp)that codes for more than 80 open reading frames(ORFs).For survival and latency in the host,a large amount of the viral proteins participate in the process of escaping the host innate immune responses and cause the host tissue damage in diverse ways.Accumulating data have demonstrated that gL mediates the viral invasion by forming the g H/ gL complex dimer,So far,it is very little known regarding the capacity of gL for HSV to escape host innate immune surveillance and to achieve latent infection.In this study,we analyzed the effects of gL which is coded by the UL1 gene of HSV-1 on the interferon I type(IFN)and the interferon-induced gene product(ISG)in the host innate immune signal pathway.The results showed that the gL significantly down-regulated the transcription of IFN-?and ISG15.On contrary,gL gene silencing by RNAi up-regulated the transcription of IFN-? and the ISG15,and thus the gL had significant effect on the transcription and translation of the related adapter-proteins and transcription factors in the anti-viral signal pathway upstream of IFN-?.To further verify the target of gL on the innate immune signal pathway,we used a confocal microscope to address if gL was able to affect the translocation of phosphorylated p65 upon NF-?B activation.Our results showed that ectopic expression of gL significantly inhibited translocation of phosphorylated p65 to the nucleus.Yet thus,the inactivation of gL by RNAi was shown to significantly recovers the inhibition on the translocation of the phosphorylated p65 to the nucleus.Further study have demonstrated that the anterior segment of gL(1-77aa)binds to the rel homology domain(RHD)of the NF-?B subunits p65,suggesting that covering the nuclear localization signal(NLS)site of p65 may cause the inhibition of the phosphorylated p65 translocation to the nucleus,,which may contribute to immune evasion.In addition,there are many ways to avoid the innate immune response of the host,including regulating cell cycle,inducing cell damage and inhibiting the expression of pro-inflammatory factors,and regulating the amount of dissolved oxygen of the cells etc.In present results showed that gL inhibited the apoptosis of the host cells and down-regulated the TNF-1 and IL-6 expression.However,gL did not affect the cell cycle and the ROS production.In addition,to further study the mechanism of gL-mediated host injury,we studied the effects of apoptosis,pathological and viral proliferation effects of the mouse tissue organ by infecting the viruses carrying the wild-type or above amino acid deletion mutant gL.The results showed that the virus carrying the gL mutant can relieve the destruction of the microtubule protein in the mouse,and cause the reduction of the cell apoptosis,the pathological damage(as shown by HE-staining,and the virus replication.