Special Report

Department of Orthopedics, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

‡Authors contributed equally

Haifeng Yu‡

Department of Pharmaceutics, School of Pharmacy, Hubei University of Science & Technology, Xianning, China

‡Authors contributed equally

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Liqiong Ding

*Author for correspondence:

E-mail Address: dinglq2021@163.com

https://orcid.org/0000-0003-0508-7531

Department of Pharmaceutics, School of Pharmacy, Hubei University of Science & Technology, Xianning, China

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Published Online:14 Apr 2023https://doi.org/10.2217/fvl-2023-0031

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Abstract

Herpes simplex virus (HSV) can cause life-threatening diseases such as herpes simplex keratitis and herpes simplex encephalitis, with considerable tissue damage resulting from viral replication. The immune response that is activated in response to infection to control viral replication may become exaggerated and contribute to this damage. An overactive inflammatory response could be controlled using immunomodulatory strategies, an ideal target for which may be the multiple pattern recognition receptors that are involved in the innate immune response to HSV, including Toll-like receptors, RIG-I-like receptors, nucleotide oligomerization domain like receptors and cGAS-STING. Here, we summarize the role of the NLRP3 inflammasome in HSV infection and discuss the potential mechanism and therapeutic strategies of targeting the NLRP3 inflammasome for HSV-related diseases.

Plain language summary

HSV can cause life-threatening conditions such as herpes simplex keratitis and herpes simplex encephalitis. The immune response to suppress viral replication may be exaggerated, leading to tissue damage. This may damage may be limited by using immunomodulatory strategies. For example, multiple receptors are involved in the innate immune response to HSV, including NLRP3, which may be ideal targets for immunomodulation. This article reviews the role of the NLRP3 inflammasome in HSV infection and discusses the mechanisms and treatment strategies utilizing the NLRP3 inflammasome in HSV-related diseases.

Tweetable abstract

Inflammation caused by HSV infection can sometimes lead to life-threatening pathologies. Studies have shown that HSV-induced inflammatory responses rely on NLRP3 inflammasome. This article reviews the role of the NLRP3 inflammasome in HSV infection.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Arduino PG, Porter SR. Herpes simplex virus type 1 infection: overview on relevant clinico-pathological features. J. Oral Pathol. Med. 37(2), 107–121 (2008).
MedlineGoogle Scholar
2. Rowe AM, Yun H, Treat BR, Kinchington PR, Hendricks RL. Subclinical herpes simplex virus type 1 infections provide site-specific resistance to an unrelated pathogen. J. Immunol. 198(4), 1706–1717 (2017).
Medline CASGoogle Scholar
3. Rowe AM, Yun H, Hendricks RL. Exposure stress induces reversible corneal graft opacity in recipients with herpes simplex virus-1 infections. Invest. Ophthalmol. Vis. Sci. 58(1), 35–41 (2017).
Medline CASGoogle Scholar
4. Wang L, Wang R, Xu C, Zhou H. Pathogenesis of herpes stromal keratitis: immune inflammatory response mediated by inflammatory regulators. Front. Immunol. 11, 766 (2020).
Medline CASGoogle Scholar
5. Gnann JW Jr, Whitley RJ. Herpes simplex encephalitis: an update. Current Infect. Dis. Rep. 19(3), 13 (2017).
MedlineGoogle Scholar
6. Bradshaw MJ, Venkatesan A. Herpes simplex virus-1 encephalitis in adults: pathophysiology, diagnosis, and management. Neurotherapeutics 13(3), 493–508 (2016).
Medline CASGoogle Scholar
7. Liu J, Qian C, Cao X. Post-translational modification control of innate immunity. Immunity 45(1), 15–30 (2016).
MedlineGoogle Scholar
8. Biswas PS, Banerjee K, Kim B, Rouse BT. Mice transgenic for IL-1 receptor antagonist protein are resistant to herpetic stromal keratitis: possible role for IL-1 in herpetic stromal keratitis pathogenesis. J. Immunol. 172(6), 3736–3744 (2004).
Medline CASGoogle Scholar
9. Keadle TL, Usui N, Laycock KA, Miller JK, Pepose JS, Stuart PM. IL-1 and TNF-alpha are important factors in the pathogenesis of murine recurrent herpetic stromal keratitis. Invest. Ophthalmol. Vis. Sci. 41(1), 96–102 (2000).
Medline CASGoogle Scholar
10. Mancini M, Vidal SM. Insights into the pathogenesis of herpes simplex encephalitis from mouse models. Mamm. Genome 29(7–8), 425–445 (2018).
Medline CASGoogle Scholar
11. Rock KL, Latz E, Ontiveros F, Kono H. The sterile inflammatory response. Annu. Rev. Immunol. 28, 321–342 (2010).
Medline CASGoogle Scholar
12. Jacobs SR, Damania B. NLRs, inflammasomes, and viral infection. J. Leukoc. Biol. 92(3), 469–477 (2012).
Medline CASGoogle Scholar
13. Kanneganti TD. Central roles of NLRs and inflammasomes in viral infection. Nat. Rev. Immunol. 10(10), 688–698 (2010).
Medline CASGoogle Scholar
14. Lamkanfi M, Kanneganti TD, Franchi L, Nunez G. Caspase-1 inflammasomes in infection and inflammation. J. Leukoc. Biol. 82(2), 220–225 (2007).
Medline CASGoogle Scholar
15. Kanneganti TD. The signposts and winding roads to immunity and inflammation. Nat. Rev. Immunol. 19(2), 81–82 (2019).
Medline CASGoogle Scholar
16. Rathinam VA, Jiang Z, Waggoner SN et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat. Immunol. 11(5), 395–402 (2010).
Medline CASGoogle Scholar
17. Karaba AH, Figueroa A, Massaccesi G, Botto S, Defilippis VR, Cox AL. Herpes simplex virus type 1 inflammasome activation in proinflammatory human macrophages is dependent on NLRP3, ASC, and caspase-1. PLOS ONE 15(2), e0229570 (2020). • HSV-1 activates inflammasome in human macrophages through an NLRP3 dependent process.
Medline CASGoogle Scholar
18. Zaki MH, Vogel P, Malireddi RK et al. The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer Cell 20(5), 649–660 (2011).
Medline CASGoogle Scholar
19. Zheng C. The emerging roles of NOD-like receptors in antiviral innate immune signaling pathways. Int. J. Biol. Macromol. 169, 407–413 (2021).
Medline CASGoogle Scholar
20. Lupfer C, Kanneganti TD. The expanding role of NLRs in antiviral immunity. Immunol. Rev. 255(1), 13–24 (2013).
MedlineGoogle Scholar
21. Amsler L, Malouli D, Defilippis V. The inflammasome as a target of modulation by DNA viruses. Future Virol. 8(4), 357–370 (2013).
CASGoogle Scholar
22. Uyar O, Dominguez JM, Bordeleau M et al. Single-cell transcriptomics of the ventral posterolateral nucleus-enriched thalamic regions from HSV-1-infected mice reveal a novel microglia/microglia-like transcriptional response. J. Neuroinflammation 19(1), 81 (2022).
Medline CASGoogle Scholar
23. Muruve DA, Petrilli V, Zaiss AK et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 452(7183), 103–107 (2008).
Medline CASGoogle Scholar
24. Wang W, Hu D, Wu C et al. STING promotes NLRP3 localization in ER and facilitates NLRP3 deubiquitination to activate the inflammasome upon HSV-1 infection. PLOS Pathog. 16(3), e1008335 (2020). •• The cGAS-STING-NLRP3 signaling pathway is critical in host defense against HSV infection.
Medline CASGoogle Scholar
25. Phelan D, Barrozo ER, Bloom DC. HSV1 latent transcription and non-coding RNA: a critical retrospective. J. Neuroimmunol. 308, 65–101 (2017).
Medline CASGoogle Scholar
26. Sivasubramanian MK, Monteiro R, Harrison KS, Plakkot B, Subramanian M, Jones C. Herpes simplex virus type 1 preferentially enhances neuro-inflammation and senescence in brainstem of female mice. J. Virol. 96(17), e0108122 (2022).
MedlineGoogle Scholar
27. Johnson KE, Chikoti L, Chandran B. Herpes simplex virus 1 infection induces activation and subsequent inhibition of the IFI16 and NLRP3 inflammasomes. J. Virol. 87(9), 5005–5018 (2013).
Medline CASGoogle Scholar
28. Hu X, Zeng Q, Xiao J et al. Herpes simplex virus 1 induces microglia gasdermin D-dependent pyroptosis through activating the NLR family pyrin domain containing 3 inflammasome. Front. Microbiol. 13, 838808 (2022).
MedlineGoogle Scholar
29. Li XD, Wu J, Gao D, Wang H, Sun L, Chen ZJ. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341(6152), 1390–1394 (2013).
Medline CASGoogle Scholar
30. Reinert LS, Lopusna K, Winther H et al. Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS. Nat. Commun. 7, 13348 (2016).
Medline CASGoogle Scholar
31. Christensen MH, Jensen SB, Miettinen JJ et al. HSV-1 ICP27 targets the TBK1-activated STING signalsome to inhibit virus-induced type I IFN expression. EMBO J. 35(13), 1385–1399 (2016).
Medline CASGoogle Scholar
32. Bodda C, Reinert LS, Fruhwurth S et al. HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection. J. Exp. Med. 217(7), e20191422 (2020).
Medline CASGoogle Scholar
33. You H, Zheng S, Huang Z, Lin Y, Shen Q, Zheng C. Herpes simplex virus 1 tegument protein UL46 inhibits TANK-binding kinase 1-mediated signaling. mBio 10(3), e00919–19 (2019).
Medline CASGoogle Scholar
34. Pan S, Liu X, Ma Y, Cao Y, He B. Herpes simplex virus 1 gamma(1)34.5 protein inhibits STING activation that restricts viral replication. J. Virol. 92(20), e01015–01018 (2018).
Medline CASGoogle Scholar
35. Wang SL, Zhao G, Zhu W et al. Herpes simplex virus-1 infection or Simian virus 40-mediated immortalization of corneal cells causes permanent translocation of NLRP3 to the nuclei. Int. J. Ophthalmol. 8(1), 46–51 (2015).
MedlineGoogle Scholar
36. Coulon PG, Dhanushkodi N, Prakash S et al. NLRP3, NLRP12, and IFI16 inflammasomes induction and caspase-1 activation triggered by virulent HSV-1 strains are associated with severe corneal inflammatory herpetic disease. Front. Immunol. 10, 1631 (2019). •• Viral virulence affects the activation of NLRP3 inflammasome.
Medline CASGoogle Scholar
37. Schwaid AG, Spencer KB. Strategies for targeting the NLRP3 inflammasome in the clinical and preclinical space. J. Med. Chem. 64(1), 101–122 (2021).
Medline CASGoogle Scholar
38. Giguere PM, Gall BJ, Ezekwe EAD Jr et al. G Protein signaling modulator-3 inhibits the inflammasome activity of NLRP3. J. Biol. Chem. 289(48), 33245–33257 (2014).
Medline CASGoogle Scholar
39. Li F, Song X, Su G et al. AT-533, a Hsp90 inhibitor, attenuates HSV-1-induced inflammation. Biochem. Pharmacol. 166, 82–92 (2019).
Medline CASGoogle Scholar
40. Jiang K, Feng J, Qi X, Ran L, Xie L. Antiviral activity of oridonin against herpes simplex virus type 1. Drug Des. Devel. Ther. 16, 4311–4323 (2022). • Oridonin alleviates herpes simplex keratitis infection in mice by inhibiting the NLRP3-inflammasome-IL-1β pathway.
MedlineGoogle Scholar
41. Coll RC, Robertson AA, Chae JJ et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 21(3), 248–255 (2015).
Medline CASGoogle Scholar
42. Jiang H, He H, Chen Y et al. Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J. Exp. Med. 214(11), 3219–3238 (2017).
Medline CASGoogle Scholar
43. Juliana C, Fernandes-Alnemri T, Wu J et al. Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome. J. Biol. Chem. 285(13), 9792–9802 (2010).
Medline CASGoogle Scholar
44. Marchetti C, Swartzwelter B, Gamboni F et al. OLT1177, a beta-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc. Natl Acad. Sci. USA 115(7), E1530–E1539 (2018).
Medline CASGoogle Scholar
45. Youm YH, Nguyen KY, Grant RW et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med. 21(3), 263–269 (2015).
Medline CASGoogle Scholar
46. Yin H, Guo Q, Li X et al. Curcumin suppresses IL-1beta secretion and prevents inflammation through inhibition of the NLRP3 inflammasome. J. Immunol. 200(8), 2835–2846 (2018).
Medline CASGoogle Scholar
47. Li Q, Feng H, Wang H et al. Licochalcone B specifically inhibits the NLRP3 inflammasome by disrupting NEK7-NLRP3 interaction. EMBO Rep. 23(2), e53499 (2022).
Medline CASGoogle Scholar
48. Kamei S, Taira N, Ishihara M et al. Prognostic value of cerebrospinal fluid cytokine changes in herpes simplex virus encephalitis. Cytokine 46(2), 187–193 (2009).
Medline CASGoogle Scholar
49. Studahl M, Rosengren L, Gunther G, Hagberg L. Difference in pathogenesis between herpes simplex virus type 1 encephalitis and tick-borne encephalitis demonstrated by means of cerebrospinal fluid markers of glial and neuronal destruction. J. Neurol. 247(8), 636–642 (2000).
Medline CASGoogle Scholar
50. Sabri F, Granath F, Hjalmarsson A, Aurelius E, Skoldenberg B. Modulation of sFas indicates apoptosis in human herpes simplex encephalitis. J. Neuroimmunol. 171(1–2), 171–176 (2006).
Medline CASGoogle Scholar
51. Chen W, Foo SS, Zaid A et al. Specific inhibition of NLRP3 in chikungunya disease reveals a role for inflammasomes in alphavirus-induced inflammation. Nat. Microbiol. 2(10), 1435–1445 (2017).
Medline CASGoogle Scholar
52. He Z, Chen J, Zhu X et al. NLRP3 inflammasome activation mediates Zika virus-associated inflammation. J. Infect. Dis. 217(12), 1942–1951 (2018).
Medline CASGoogle Scholar
53. Kaushik DK, Gupta M, Kumawat KL, Basu A. NLRP3 inflammasome: key mediator of neuroinflammation in murine Japanese encephalitis. PLOS ONE 7(2), e32270 (2012).
Medline CASGoogle Scholar

Vol. 18, No. 4

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History

Received 11 February 2023

Accepted 27 March 2023

Published online 14 April 2023

Published in print March 2023

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Keywords

Author contributions

Y Ding and HF Yu wrote the manuscript. LQ Ding conceived the work and revised the manuscript. All authors read and approved the final manuscript.

Financial & competing interests disclosure

This work was supported by the Scientific Research Project of the Education Department of Hubei Province (Q20212805) and the Initial Scientific Research Fund of PhDs in Hubei University of Science and Technology (BK202120). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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The involvement of NLRP3 inflammasome in herpes simplex virus infection and treatment

Abstract

Plain language summary

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References