HSV-1 Infection Of Dendritic Cells And Its Interference Mechanism On Host Antiviral Immune Response

Herpes simplex virus type 1(HSV-1)infection is a serious health problem that affects human physiology and psychology.According to statistics from the World Health Organization,3.7 billion people who under 50 years age(67%)have infected HSV-1,and the infection rate among some people can reach 100%.HSV-1 infection is mostly asymptomatic in the case,and mild symptoms may occur in herpes,herpes keratitis and encephalitis.Newborn infection HSV will have systemic diseases,brain infections,or skin infections,and untimely treatment lead to the mortality rate as high as 85%.HSV-1 infection leads to characteristic pathological lesions and an immune response in infected individuals,and the biological features of HSV-1 have impeded the development of antiviral drugs and preventive vaccines.Therefore,in order to provide more theoretical basis for the development of HSV-1 vaccines and preventive and curative drugs,we need to deeply explore the mechanism of HSV-1 interference with the body’s immunity.Previous studies have suggested that HSV-1 may enter dendritic cells(Dendritic Cells,DC)through the interaction of the viral membrane glycoprotein gD with HVEM.During this process,dendritic cells dynamically mature from an undifferentiated state to a differentiated state as they receive antigenic stimuli,migrate to the lymph nodes and secrete various immunoregulatory molecules and express distinct cellular surface markers.All of these findings indicate that the role of dendritic cells in the innate immune response based upon their intrinsic functions might be affected by viral infection and intracellular replication,which might contribute to the activation and production of adaptive immunity.In this sense,more knowledge about the interaction between HSV-1 and dendritic cells during viral infection is needed to elucidate host pathology outcomes and the immunologic mechanism induced during HSV-1 infection.In the current study,HVEM gene-deficient mice were used to investigate the interaction between HSV-1 and dendritic cells and the impact of viral infection of these cells on outcomes after pathologic infection and immunologic effects involving innate immunity and specific antiviral immunity.We first determined that HSV-1 is able to infect dendrites through the interaction between gD and HVEM and replication therein based on the analysis of the proliferation kinetics of virus infection in mouse JAWSII-dendritic cells and the detection of innate immunity-related molecules dendritic cells.This event will affect the innate immune response of dendritic cells to the virus and the process of transmitting viral antigenic information to the adaptive immune system.Secondly,we analyzed the replication characteristics of HSV-1 entering dendritic cells in epithelial tissues through HVEM receptors,found that the immunofluorescence colocalization percentage of HSV-1 virus antigen in dendritic cells(CD11c+label)from skin of WT C57 mice within 24 and 48 hours after infection was 3 to 4 times higher than that of HVEM-/-mice,and the viral load was 100 times higher than in HVEM-/-mice.In addition,the transcription level of IFN-γ and IFN-α,an important immune regulator and indicator that exerts antiviral effects,was higher in HVEM-/-mice than in C57 mice.The expression of some inflammatory factors,including TNF-α,IL-6 and GM-CSF,was upregulated in HVEM-/-mice,and the expression of IL-12 and IL-23α,which stimulate the proliferation of Thl and Th 17 cells showed a similar trend of upregulation in this group.Conversely,the transcription level of the chemokines CCL28 and CXCL12,which maintain the stability of innate immunity,was higher in C57 mice than in HVEM-/-mice.At the same time,dendritic cells isolated from the epithelial tissues of C57 mice were cultured and infected with HSV-1 in in vitro,which support the results of the mouse experiments.In addition,the acute phase infection of HVEM-/-mice showed typical pathological changes and high mortality in the early stage.These data indicate that HSV-1 infection of dendritic cells may lead to the suppression of some important immunoregulatory factors and inflammatory factors,which may lead to a reduction of pathological phenotypes in the acute phase of infection and provide an environment that allows the virus to replicate and spread in tissues.We further analyzed the interference of HSV-1 infected dendritic cells in lymph nodes.The results showed that the colocalization percentage of viral antigens in dendritic cells from lymph node tissue of HVEM-/-mice was significantly higher than that in C57 mice.At the same time,the viral load in the lymph nodes of HVEM-/-mice increased while that of C57 mice remained unchanged.Furthermore,the transcription levels of various signaling molecules including ROXγt,Foxp3,T-bet,IKKβ,p38,STAT1,3,6,which related to T and B cells proliferation in the lymph nodes,were found sharp rising since day 6 post infection in HVEM-/-mice compared to WT C57 mice,and HVEM-/-mice also showed stronger neutralizing antibody titers and specific CTL responses.These indicators mean that HSV-1 infection of dendritic cells may suppress innate immunity,resulting in a weakened specific antiviral immune response,which is due to the interference effect of viral infection strategies on the immune system.Current studies have shown that the interference effect of HSV-1 was resulted from its infection of dendritic cells and modification of their immune effect.This mechanism increases the likelihood that the virus will survive and spread in return for alleviation of pathologic lesions in the host,which seemed to suggest a balance resulting from the interaction between viral infection and the host response.