When herpes simplex virus encephalitis meets antiviral innate immunity

Abstract

Herpes simplex virus (HSV) is the most common pathogen of infectious encephalitis, accounting for nearly half of the confirmed cases of encephalitis. Its clinical symptoms are often atypical. HSV PCR in cerebrospinal fluid is helpful for diagnosis, and the prognosis is usually satisfactory after regular antiviral treatment. Interestingly, some patients with recurrent encephalitis have little antiviral effect. HSV PCR in cerebrospinal fluid is negative, but glucocorticoid has a significant effect after treatment. Specific antibodies, such as the NMDA receptor antibody, the GABA receptor antibody, and even some unknown antibodies, can be isolated from cerebrospinal fluid, proving that the immune system contributes to recurrent encephalitis, but the specific mechanism is still unclear. Based on recent studies, we attempt to summarize the relationship between herpes simplex encephalitis and innate immunity, providing more clues for researchers to explore this field further.

Keywords: NMDAR encephalitis; autoimmune encephalitis; herpes simplex virus; immunotherapy; innate immune.

Figure 1

Viral envelope glycoproteins mediate binding with the cell membrane. Viral DNA enters the nucleus and transcribes and translates viral particle accessories as the envelope merges with the cell membrane. Eventually, intact virions leave the cell by exocytosis.

Figure 2

DAI, cGAS, IFI16, and TLR3 are nucleic acid sensing mechanisms of the virus that recruit and activate TBK1, which in turn activates IRF3, resulting in the expression of interferon or cytokines. In addition, DAI can also recruit RIP1/3 to promote gene transcription and expression, and TLR3 can activate NF-κB and AP-1 and induce the production of interferon and inflammatory factors.

Figure 3

HSV into the central nervous system can cause infection of neurons, which is referred to as primary infection. Both viral particles and infected cells can recruit B and T cells. Antibodies produced by B cells can neutralize virus particles, and T cells can exert cytotoxicity to kill infected cells. Due to the similar structure of viral surface antigens to self-tissue, antibodies derived from the primary infection may attack healthy neurons. And cell disintegration leads to self-antigen exposure, induces B cells to produce antibodies, and further attacks self-cells, which is called post-infectious encephalitis or autoimmune encephalitis.