Study On The Role Of HVEM In Herpes Simplex Virus Type 1 Infection

HSV-1 infection spreads widely around the world and causes various herpesous diseases.At present,only antiviral drugs such as acyclovir can effectively control the symptoms of viral infection.Antiviral drugs cannot prevent the primary infection the latent infection and recurrent infection of herpes virus.Also,antiviral drugs are easy to develop drug resistance.In view of the unknown complex infectious and pathogenic mechanisms of HSV-1 and the immune mechanisms after HSV-1 infection,the development of HSV-1 vaccine and therapeutic drugs is faced with great challenges.Studies have shown that after HSV-1 infection,its glycoproteins and DNA can be recognized by the host receptor,thus initiating the innate immune response,followed by activating the humoral and cellular immune responses.As the glycoprotein gD receptor to enter into cells of HSV-1,HVEM is expressed on a variety of immune cells,especially on dendritic cells which play an important regulatory role in immune response.Therefore,it is not clear how HVEM participates in the protective immune response against HSV-1 infection,especially its role in innate immunity,specific antibodies and cellular immune response.In the first part,the differences between HVEM-/-mice and wild-type C57BL/6 mice were compared in clinical manifestations,pathological changes and viral load after infected HSV-1 strain McKrae in different ways.The results showed that there were no significant differences in clinical manifestations,pathological changes and viral load between HVEM-/-mice and C57BL/6 mice after intramuscular injection,while there were significant differences in clinical manifestations,pathological changes and viral load between HVEM-/-mice and C57BL/6 mice after intradermal injection.The receptor requirements of HSV-1 entry into cells may depend on the route of infectionSince there was no significant difference between HVEM-/-mice and C57BL/6 mice after intramuscular injection,we performed transcriptome sequencing analysis on the dendritic cells of infected mice.The results showed that After HSV-1 infection,there were significant differences in gene expression in the dendritic cells of HVEM-/-mice and C57BL/6 mice,especially 7 days after infection.The dendritic cells of HVEM-/-mouse showed significant inhibition of autophagy,NF-?B signaling pathway,IFN-I secretion,and increased T cell proliferation and activation after infection with HSV-1 McKrae strain in comparison with C57BL/6 mice's.On the basis of transcriptome sequencing results,we used the previously constructed mutant strain M3 which has partial knockout of ul17,ul41 and LAT to immunize mice and then the mice were infected by McKrae,the wild-type strain of HSV-1.The clinical manifestations,pathological changes,viral load,neutralizing antibody response and specific cell responses of the infected mice were compared.The results showed that HVEM-/-mice did not detect B cell neutralizing antibody response after M3 immunization,but specific IFN-y and IL-4 cell responses were detected,and the trend of specific IL-4 cells was similar to that of wild-type mice,while the trend of specific IFN-y cells was opposite to that of wild-type mice.After immunization,when mice were infected with McKrae,the HVEM-/-mice and C57BL/6 mice showed no obvious pathological changes or clinical symptoms,and the viral load of nervous system tissues was significantly decreased.After infection,HVEM-/-mice showed specific IFN-?and IL-4 cell responses that increased over time,while C57BL/6 mice showed the opposite.In summary,HVEM plays a specific role in regulating the host immune system response against HSV-1 infection due to its important role in mediating the entry of viruses into various immune cells.As an immune signaling molecule,HVEM participates in the immune response and regulates the innate and adaptive immune responses by regulating autophagy,NF-?B signaling pathways,and T cell proliferation and differentiation,which forms the comprehensive effect of HSV-1 on the immune system and the characteristics of immune response against HSV-1 formed by the immune system under this premise.The understanding of this mechanism will be helpful for the research of HSV-1 drugs and vaccines.Therefore,this study provides a theoretical basis for elucidate the mechanism of the process of HSV-1 infection and the immune response mechanism after HSV-1 infection,and provides a new idea for the research of HSV-1 vaccines and therapeutic drugs.