Adiva Sahar

Introduction. Herpes simplex viruses (HSV-1/HSV-2) are neurotropic human pathogens. HSV infection of the CNS can cause herpes simplex encephalitis, which is associated with high mortality and neurological sequelae.¹ OPTN is a multifunctional protein involved in the regulation of selective autophagy and inflammatory signaling and protection from cell death.²  Methods. Multiple cell lines and mice were used as in vitro and in vivo experimental models to determine the regulatory roles of OPTN. Sophisticated molecular technologies including qRT-PCR, western blot, and immunofluorescence were employed to reveal the inherent mechanisms.  Results. In the TG, VP16 driven by latent program promoter resulted in a temporal shift in the production of infectious virus, indicating that de novo VP16 expression mediates entry into the lytic cycle.³ Following HSV-1 infection, OPTN deficient cells expressed increased levels of VP16 and gB and production of infectious virus. Thus, OPTN is essential for the selective degradation of essential HSV-1 proteins and restricts HSV replication.⁴ Following HSV-2 infection, CD4+ T cells frequency was increased in OPTN+/+ tissues, while a dysregulated pattern of CD4+ cells and higher CD8+ T cell frequency was seen in OPTN-/- tissues.⁶ OPTN-/- lymphoid cells expressed higher levels of CD8+ T cells and Il-17A expression in T cell populations. This suggests that OPTN-/- TG is subject to severe, chronic, and abnormal inflammation, which may result from Il-17 signaling and CD8+ T cell infiltration.⁷ Following HSV-1 infection, OPTN-/- draining lymph nodes had decreased proinflammatory cytokine expression and OPTN-/- mice brainstems had increased expression of proinflammatory markers and fewer T cells. This suggests that the loss of OPTN disrupts T cell infiltration, which dysregulates the host immune response and exacerbates inflammation.⁴ In Ao-stimulated microglial cells, OPTN deficiency facilitated the activation of AIM2 inflammasomes., indicating that OPTN alleviates the effects of Ao on activating AIM2 inflammasomes.⁸ Following infection, neuron death was undetectable in OPTN+/+ tissue, but high in OPTN-/- tissue, suggesting that OPTN protects the CNS from neuroinvasion and neurodegeneration. OPTN negatively regulates necroptosis by targeting RIPK for autophagic degradation.⁴  Conclusion. OPTN is closely linked with optimal immune function and neuronal survival. Defects in OPTN functions compounded by HSV infection have the potential to cause accelerated neuronal damage. Viral infection of the CNS has been hypothesized to contribute to the etiology of neurodegenerative disorders, and defects in autophagy may synergize with infection and subclinical neuroinflammation to accelerate neurodegeneration. Treatment with the RIPK1 inhibitor, Nec1s, was shown to rescue mice from acute necroptosis. Nec1s may be a potential drug candidate to treat viral encephalitis. T-cell mediated inflammasomes may be a potential therapeutic target to alleviate HSV-associated symptoms.

1. Marcocci ME, Napoletani G, Protto V, et al. Herpes Simplex Virus-1 in the Brain: The Dark Side of a Sneaky Infection. Trends Microbiol. 2020;28(10):808-820. doi:10.1016/j.tim.2020.03.003
2. Slowicka K, van Loo G. Optineurin Functions for Optimal Immunity. Front Immunol. 2018;9:769. doi:10.3389/fimmu.2018.00769
3. Sawtell NM, Thompson RL. De Novo Herpes Simplex Virus VP16 Expression Gates a Dynamic Programmatic Transition and Sets the Latent/Lytic Balance during Acute Infection in Trigeminal Ganglia. PLoS Pathog. 2016;12(9):1-27. doi:10.1371/journal.ppat.1005877
4. Ames J, Yadavalli T, Suryawanshi R, et al. OPTN is a host intrinsic restriction factor against neuroinvasive HSV-1 infection. Nat Commun. 2021;12(1):1-14. doi:10.1038/s41467-021-25642-z
5. Waisner H, Kalamvokia M. The ICP0 Protein of Herpes Simplex Virus 1 (HSV-1) Downregulates Major Autophagy Adaptor Proteins Sequestosome 1 and Optineurin during the Early Stages of HSV-1 Infection. Virology. 2019;93(21). doi:10.1128/JVI.01258-19
6. Patil CD, Suryawanshi R, Ames J, et al. Intrinsic Antiviral Activity of Optineurin Prevents Hyperproliferation of a Primary Herpes Simplex Virus Type 2 Infection. J Immunol. 2022;208(1):63 LP – 73. doi:10.4049/jimmunol.2100472
7. Ames J, Yadavalli T, Patil C, Hopkins J, Bhattacharya I, Shukla D. OPTN limits herpes stromal keratitis severity and demyelination through negative regulation of IL-17 and hyperinflammatory T-cell response. bioRxiv. Published online January 1, 2021:2021.11.29.470418. doi:10.1101/2021.11.29.470418
8. Cao LL, Guan PP, Zhang SQ, Yang Y, Huang XS, Wang P. Downregulating expression of OPTN elevates neuroinflammation via AIM2 inflammasome- and RIPK1-activating mechanisms in APP/PS1 transgenic mice. J Neuroinflammation. 2021;18(1):1-24. doi:10.1186/s12974-021-02327-4