Characterization Of The Immunologic Phenotype Of Dendritic Cells Infected With Herpes Simplex Virus 1 During The Antiviral Immune Response

Herpes simplex virus type 1(HSV-1)infection is a critical public health issue.According to the World Health Organization,about 70%of the population is currently infected with the HSV-1 virus.Infection with this pathogen can cause herpes labialis,herpangina,herpetic encephalitis and other diseases,as well as,post-infection morbidity and mortality increase in neonates and immunocompromised patients.Virus leads to lifelong infection by establishing latency in neurons,reactivating,and promoting recurrent disease and new infections.The reason for the persistence of HSV-1 in the body has been determined to be the fact that the virus has multiple links to evade innate and adaptive immune responses.Dendritic cells,is a bridge connecting innate immunity and adaptive immunity.As an important innate immune cell,it plays an important role in the induction and presentation of antiviral immune responses.HSV-1 can infect some dendritic cells due to the viral membrane glycoprotein D binding to HVEM receptor in membrane of those cells,which become the event in the virus’ strategy to interfere with the host’s immune system.We previously generated an HSV-1 mutant strain M6,with partial deletions in ul7,u141,LAT,us3,usl1 and usl2 by CRISPR/Cas9 Gene-Editing Technology,which not only produced an attenuated phenotype in mice and rhesus monkeys,but also can induce neutralizing antibody response and active cellular immune response.As well as,attenuated strain M6 play a protective role against re-infection of pathogens,and has good immunogenicity.This suggests that the attenuated strain cannot form a clear interference effect on the body’s immune system during infection.Therefore,we used the attenuated strain M6 as a reference to explored the possible mechanism of HSV-1 infection of dendritic cells in interfering with innate and adaptive immunity.This work showed that HVEM receptors in the membrane of dendritic cells can mediate infection of wild strain and attenuated strain M6,and,infected dendritic cells by both viruses in local tissues of animals can express changes in transcriptional profiles associated with innate immune and inflammatory responses.Interestingly,the infection of two strains in pDCs and cDCs enable of promotion the cells differentiation to phenotype of CD103+,but showing varied transcription profiles associated with innate immunity and inflammatory responses;further in-depth analysis of transcript sequencing indicated that the HSV-1 wild strain interfered with dendritic cells’ immune function and affects the antigen-presenting capacity and activation of T cells and B cells.After that,the dendritic cells infected with the wild strain and the attenuated strain M6 were transfer into mice by the tail vein,and it was found that there were obvious differences in the immune response phenotypes caused by the two strains.The virus load in each tissue of the mice in the attenuated M6 group was lower than that in the wild strain group,and the specific IFN-γ and IL-4 cell responses induced were higher than those in the wild strain group,which implied that the activation of T cells in the lymph node tissue is inhibited or attenuated for the wild strain group mice.The mice of the attenuated strain M6 transfer group had a certain protective effect by the nasal challenge on the 28th day after the transfer.Not only showed specific IFN-y and IL-4 cell responses but also induced higher humoral immunity;while the wild-type strain mice showed obvious clinical symptoms such as death,weight loss,humpback and trichiasis after challenge.The induced cellular immune responses and humoral immune responses were significantly lower than those of the attenuated M6 mice.In conclusion,the results of this research indicate that HSV-1 can infect some dendritic cells due to the viral membrane glycoprotein D binding to HVEM receptor in membrane of those cells,which become the one of event in the virus’ strategy to interfere with the host’s immune system and and affects the transcription of various genes in the cells,thereby altering the immunological characteristics of mouse dendritic cells to recognize viral antigens and present antigens to T cells,resulting in immunophenotypic defects.The results of this research provide information for demonstrating the immune response mechanism of HSV-1 infected individuals unable to eliminate the virus and prevent re-infection after infection,and provide new insight for the research of HSV-1 vaccines and therapeutic drugs.