Mice with type I interferon signaling deficiency are prone to epilepsy upon HSV-1 infection

Wei Yang; Chong-Yang Tang; Dong-Ying Fan; Yi-Song Wang; Pei-Gang Wang; Jing An; Guo-Ming Luan

doi:10.1016/j.virs.2024.01.002

April 2024

. doi: 10.1016/j.virs.2024.01.002

Citation: Wei Yang, Chong-Yang Tang, Dong-Ying Fan, Yi-Song Wang, Pei-Gang Wang, Jing An, Guo-Ming Luan. Mice with type I interferon signaling deficiency are prone to epilepsy upon HSV-1 infection .VIROLOGICA SINICA, 2024, 39(2) : 251-263. http://dx.doi.org/10.1016/j.virs.2024.01.002

I型干扰素信号缺乏的小鼠在感染HSV-1后易患癫痫

杨威 ^a,b ,
唐重阳 ^c ,
范东瀛 ^d ,
王一松 ^d ,
王培刚 ^d ,
安静 ^b,d ,
栾国明 ^a,b,c,e,,

a. 首都医科大学附属北京三博脑科医院, 北京市癫痫重点实验室;
b. 首都医科大学北京脑疾病研究所;
c. 首都医科大学附属北京三博脑科医院癫痫中心神经外科;
d. 首都医科大学基础医学院病原生物学学系;
e. 北京脑科学与类脑研究所。

通讯作者： 栾国明, luangm@ccmu.edu.cn
收稿日期： 2023-08-09
录用日期： 2024-01-09

摘要

病毒性脑炎仍然是全球公共卫生安全的重大威胁。在课题组前期研究中，我们发现拉斯穆森脑炎（Rasmussen’s encephalitis，RE）患者的脑组织中IFN-β、STING和IFI16等多种抗病毒关键基因的表达量显著降低。这种脑炎是一种罕见的慢性神经系统疾病，好发于儿童，其典型临床特征是单侧半球脑萎缩。此外，课题组还发现人类疱疹病毒（Human herpes viruses，HHVs）的累积病毒感染评分与RE的单半球萎缩显著正相关。I型干扰素（IFN-I）信号通过与IFN-α/β受体（IFNAR）结合发挥作用，对抗感染固有免疫至关重要。在本研究中，我们通过单侧眼周注射使野生型（Wild type，WT）小鼠及IFNAR缺陷的A6小鼠感染单纯疱疹病毒1型（Herpes simplex virus 1，HSV-1），以探究IFN-I信号传导与HHVs诱导的脑损伤之间的关系。虽然所有小鼠脑组织都表现出典型的病毒性脑炎病变，但仅有A6小鼠表现出HSV诱导的癫痫。我们进一步对小鼠脑组织进行RNA-Seq分析，并通过功能富集分析和蛋白质-蛋白质相互作用网络揭示了四种与HSV诱导的癫痫症状呈正相关的基因模块。此外，我们还鉴定了10与癫痫发作关联最为密切的关键基因。本研究表明，IFN-I信号通路可以有效抑制HHVs诱导的神经症状和脑组织病理损害，从而证实了RE和其他HHVs脑炎中IFN-I信号通路激活不足与脑萎缩之间的正相关性。
- I型干扰素信号通路
- , 人类疱疹病毒
- , 拉斯穆森脑炎

Mice with type I interferon signaling deficiency are prone to epilepsy upon HSV-1 infection

Wei Yang ^a,b ,
Chong-Yang Tang ^c ,
Dong-Ying Fan ^d ,
Yi-Song Wang ^d ,
Pei-Gang Wang ^d ,
Jing An ^b,d ,
Guo-Ming Luan ^a,b,c,e,,

a. Beijing Key Laboratory of Epilepsy, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China;
b. Beijing Institute for Brain Disorders, Capital Medical University, Beijing, 100093, China;
c. Department of Neurosurgery, Epilepsy Center, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China;
d. Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China;
e. Chinese Institute for Brain Research, Beijing, 102206, China

Corresponding author: Guo-Ming Luan, luangm@ccmu.edu.cn
Received Date: 09 August 2023
Accepted Date: 09 January 2024

Abstract

Viral encephalitis continues to be a significant public health concern. In our previous study, we discovered a lower expression of antiviral factors, such as IFN-β, STING and IFI16, in the brain tissues of patients with Rasmussen's encephalitis (RE), a rare chronic neurological disorder often occurred in children, characterized by unihemispheric brain atrophy. Furthermore, a higher cumulative viral score of human herpes viruses (HHVs) was also found to have a significant positive correlation with the unihemispheric atrophy in RE. Type I IFNs (IFN-I) signaling is essential for innate anti-infection response by binding to IFN-α/β receptor (IFNAR). In this study, we infected WT mice and IFNAR-deficient A6 mice with herpes simplex virus 1 (HSV-1) via periocular injection to investigate the relationship between IFN-I signaling and HHVs-induced brain lesions. While all mice exhibited typical viral encephalitis lesions in their brains, HSV-induced epilepsy was only observed in A6 mice. The gene expression matrix, functional enrichment analysis and protein-protein interaction network revealed four gene models that were positively related with HSV-induced epilepsy. Additionally, ten key genes with the highest scores were identified. Taken together, these findings indicate that intact IFN-I signaling can effectively limit HHVs induced neural symptoms and brain lesions, thereby confirming the positive correlation between IFN-I signaling repression and brain atrophy in RE and other HHVs encephalitis.
- IFN-I signaling
- , Human herpes viruses (HHVs)
- , Rasmussen's encephalitis (RE)

References
1. Adkins, B., Leclerc, C., Marshall-Clarke, S., 2004. Neonatal adaptive immunity comes of age. Nat. Rev. Immunol. 4, 553-564.
2. Armangue, T., Spatola, M., Vlagea, A., Mattozzi, S., Carceles-Cordon, M., Martinez-Heras, E., Llufriu, S., Muchart, J., Erro, M.E., Abraira, L., Moris, G., Monros-Gimenez, L., Corral-Corral, I., Montejo, C., Toledo, M., Bataller, L., Secondi, G., Arino, H., Martinez-Hernandez, E., Juan, M., Marcos, M.A., Alsina, L., Saiz, A., Rosenfeld, M.R., Graus, F., Dalmau, J., 2018. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis:a prospective observational study and retrospective analysis. Lancet Neurol. 17, 760-772.
3. Barry, M.A., Reynolds, J.E., Eastman, A., 1993. Etoposide-induced apoptosis in human HL-60 cells is associated with intracellular acidification. Cancer Res. 53, 2349-2357.
4. Barseem, N.F., Khattab, E., Mahasab, M.M., 2020. IL-1beta-31/IL1-RA genetic markers association with idiopathic generalized epilepsy and treatment response in a cohort of Egyptian population. Int. J. Neurosci. 130, 348-354.
5. Bayanova, M., Bolatov, A.K., Bazenova, A., Nazarova, L., Nauryzbayeva, A., Tanko, N.M., Rakhimova, S., Satvaldina, N., Samakyzy, D., Kozhamkulov, U., Kairov, U., Akilzhanova, A., Sarbassov, D., 2023. Whole-Genome Sequencing Among Kazakhstani Children with Early-Onset Epilepsy Revealed New Gene Variants and Phenotypic Variability. Mol. Neurobiol. 60, 4324-4335.
6. Bevilacqua, P.C., Cech, T.R., 1996. Minor-groove recognition of double-stranded RNA by the double-stranded RNA-binding domain from the RNA-activated protein kinase PKR. Biochemistry. 35, 9983-9994.
7. Bien, C.G., Widman, G., Urbach, H., Sassen, R., Kuczaty, S., Wiestler, O.D., Schramm, J., Elger, C.E., 2002. The natural history of Rasmussen's encephalitis. Brain. 125, 1751-1759.
8. Caruso, J.M., Tung, G.A., Gascon, G.G., Rogg, J., Davis, L., Brown, W.D., 2000. Persistent preceding focal neurologic deficits in children with chronic Epstein-Barr virus encephalitis. J. Child Neurol. 15, 791-796.
9. Cathcart, H.M., Zheng, M., Covar, J.J., Liu, Y., Podolsky, R., Atherton, S.S., 2011. Interferon-gamma, macrophages, and virus spread after HSV-1 injection. Invest. Ophthalmol. Vis. Sci. 52, 3984-3993.
10. Chin, C.H., Chen, S.H., Wu, H.H., Ho, C.W., Ko, M.T., Lin, C.Y., 2014. cytoHubba:identifying hub objects and sub-networks from complex interactome. BMC Syst. Biol. 8 Suppl 4, S11.
11. Dagsdottir, H.M., Sigurethardottir, B., Gottfreethsson, M., Kristjansson, M., Love, A., Baldvinsdottir, G.E., Guethmundsson, S., 2014. Herpes simplex encephalitis in Iceland 1987-2011. Springerplus. 3, 524.
12. Damjanac, M., Page, G., Ragot, S., Laborie, G., Gil, R., Hugon, J., Paccalin, M., 2009. PKR, a cognitive decline biomarker, can regulate translation via two consecutive molecular targets p53 and Redd1 in lymphocytes of AD patients. J. Cell Mol. Med. 13, 1823-1832.
13. Davidson, E.H., Erwin, D.H., 2006. Gene regulatory networks and the evolution of animal body plans. Science. 311, 796-800.
14. Der SD, Yang, Y.L., Weissmann, C., Williams, B.R., 1997. A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis. Proc. Natl. Acad. Sci. U. S. A. 94, 3279-3283.
15. Dijkstra, S., Kooij, G., Verbeek, R., van der Pol, S.M., Amor, S., Geisert, E.J., Dijkstra, C.D., van Noort, J.M., Vries, H.E., 2008. Targeting the tetraspanin CD81 blocks monocyte transmigration and ameliorates EAE. Neurobiol. Dis. 31, 413-421.
16. Doja, A., Bitnun, A., Ford, J.E., Richardson, S., Tellier, R., Petric, M., Heurter, H., MacGregor, D., 2006. Pediatric Epstein-Barr virus-associated encephalitis:10-year review. J. Child Neurol. 21, 384-391.
17. Feng, K., Zheng, X., Wang, R., Gao, N., Fan, D., Sheng, Z., Zhou, H., Chen, H., An, J., 2020. Long-Term Protection Elicited by a DNA Vaccine Candidate Expressing the prM-E Antigen of Dengue Virus Serotype 3 in Mice. Front. Cell Infect. Microbiol. 10, 87.
18. Finsterer, J., 2022. Intractable Epilepsy in Maternally Inherited Leigh Syndrome (MILS) Due to the Sporadic Variant m.8993T>G in MT-ATP6:A Case Report. Cureus. 14, e22716.
19. Gil, J., Esteban, M., 2000. Induction of apoptosis by the dsRNA-dependent protein kinase (PKR):mechanism of action. Apoptosis. 5, 107-114.
20. Gill, N., Chenoweth, M.J., Verdu, E.F., Ashkar, A.A., 2011. NK cells require type I IFN receptor for antiviral responses during genital HSV-2 infection. Cell Immunol. 269, 29-37.
21. Guo, Y., Jiang, L., 2019. Cytomegalovirus encephalitis in immunocompetent infants:A 15-year retrospective study at a single center. Int. J. Infect. Dis. 82, 106-110.
22. Gurses, C., Azakli, H., Alptekin, A., Cakiris, A., Abaci, N., Arikan, M., Kursun, O., Gokyigit, A., Ustek, D., 2014. Mitochondrial DNA profiling via genomic analysis in mesial temporal lobe epilepsy patients with hippocampal sclerosis. Gene. 538, 323-327.
23. Hasankhani, A., Bahrami, A., Sheybani, N., Aria, B., Hemati, B., Fatehi, F., Ghaem, M.F.H., Javanmard, G., Rezaee, M., Kastelic, J.P., Barkema, H.W., 2021. Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic. Front. Immunol. 12, 789317.
24. Hjalmarsson, A., Blomqvist, P., Skoldenberg, B., 2007. Herpes simplex encephalitis in Sweden, 1990-2001:incidence, morbidity, and mortality. Clin. Infect. Dis. 45, 875-880.
25. Huang, W., Bartosch, A.M., Xiao, H., Maji, S., Youth, E., Flowers, X., Leskinen, S., Tomljanovic, Z., Iodice, G., Boyett, D., Spinazzi, E., Menon, V., McGovern, R.A., McKhann, G.M., Teich, A.F., 2021. An immune response characterizes early Alzheimer's disease pathology and subjective cognitive impairment in hydrocephalus biopsies. Nat. Commun. 12, 5659.
26. Hugon, J., Paquet, C., 2021. The PKR/P38/RIPK1 Signaling Pathway as a Therapeutic Target in Alzheimer's Disease. Int. J. Mol. Sci. 22, 3136.
27. Karin, M., 2006. Nuclear factor-kappaB in cancer development and progression. Nature. 441, 431-436.
28. Kuerten, S., Javeri, S., Tary-Lehmann, M., Lehmann, P.V., Angelov, D.N., 2008. Fundamental differences in the dynamics of CNS lesion development and composition in MP4- and MOG peptide 35-55-induced experimental autoimmune encephalomyelitis. Clin. Immunol. 129, 256-267.
29. Kytovuori, L., Karppa, M., Tuominen, H., Uusimaa, J., Saari, M., Hinttala, R., Majamaa, K., 2017. Case report:a novel frameshift mutation in the mitochondrial cytochrome coxidase II gene causing mitochondrial disorder. BMC Neurol. 17, 96.
30. Langfelder, P., Horvath, S., 2008. WGCNA:an R package for weighted correlation network analysis. BMC Bioinformatics. 9, 559.
31. Licchetta, L., Ferri, L., La Morgia, C., Zenesini, C., Caporali, L., Lucia, V.M., Minardi, R., Fulitano, D., Di Vito, L., Mostacci, B., Alvisi, L., Avoni, P., Liguori, R., Tinuper, P., Bisulli, F., Carelli, V., 2021. Epilepsy in MT-ATP6-related mils/NARP:correlation of elettroclinical features with heteroplasmy. Ann. Clin. Transl. Neurol. 8, 704-710.
32. Lin, S.H., Arai, A.C., Espana, R.A., Berridge, C.W., Leslie, F.M., Huguenard, J.R., Vergnes, M., Civelli, O., 2002. Prolactin-releasing peptide (PrRP) promotes awakening and suppresses absence seizures. Neuroscience. 114, 229-238.
33. Liu, D., Wang, X., Wang, Y., Wang, P., Fan, D., Chen, S., Guan, Y., Li, T., An, J., Luan, G., 2018. Detection of EBV and HHV6 in the Brain Tissue of Patients with Rasmussen's Encephalitis. Virol. Sin. 33, 402-409.
34. Maere, S., Heymans, K., Kuiper, M., 2005. BiNGO:a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics. 21, 3448-3449.
35. Mancuso, G., Midiri, A., Biondo, C., Beninati, C., Zummo, S., Galbo, R., Tomasello, F., Gambuzza, M., Macri, G., Ruggeri, A., Leanderson, T., Teti, G., 2007. Type I IFN signaling is crucial for host resistance against different species of pathogenic bacteria. J. Immunol. 178, 3126-3133.
36. Nogusa, S., Thapa, R.J., Dillon, C.P., Liedmann, S., Oguin, T.R., Ingram, J.P., Rodriguez, D.A., Kosoff, R., Sharma, S., Sturm, O., Verbist, K., Gough, P.J., Bertin, J., Hartmann, B.M., Sealfon, S.C., Kaiser, W.J., Mocarski, E.S., Lopez, C.B., Thomas, P.G., Oberst, A., Green, D.R., Balachandran, S., 2016. RIPK3 Activates Parallel Pathways of MLKL-Driven Necroptosis and FADD-Mediated Apoptosis to Protect against Influenza A Virus. Cell Host Microbe. 20, 13-24.
37. Otasek, D., Morris, J.H., Boucas, J., Pico, A.R., Demchak, B., 2019. Cytoscape Automation:empowering workflow-based network analysis. Genome Biol. 20, 185.
38. Pang, I., Singhabahu, S., Novitzky-Basso, I., Mazzulli, T., Husain, S., Mattsson, J., 2022. Intrathecal cytomegalovirus immunoglobulin for CMV encephalitis post allogeneic stem cell transplantation. IDCases. 29, e1608.
39. Pollard, J.R., Eidelman, O., Mueller, G.P., Dalgard, C.L., Crino, P.B., Anderson, C.T., Brand, E.J., Burakgazi, E., Ivaturi, S.K., Pollard, H.B., 2012. The TARC/sICAM5 Ratio in Patient Plasma is a Candidate Biomarker for Drug Resistant Epilepsy. Front. Neurol. 3, 181.
40. Pradeep, K., Sinha, S., Mahadevan, A., Saini, J., Arivazhagan, A., Bharath, R.D., Bindu, P.S., Jamuna, R., Rao, M.B., Govekar, S., Ravikumar, B.V., Chandramouli, B.A., Satishchandra, P., 2016. Clinical, electrophysiological, imaging, pathological and therapeutic observations among 18 patients with Rasmussen's encephalitis. J. Clin. Neurosci. 25, 96-104.
41. Rosato, P.C., Katzenell, S., Pesola, J.M., North, B., Coen, D.M., Leib, D.A., 2016. Neuronal IFN signaling is dispensable for the establishment of HSV-1 latency. Virology. 497, 323-327.
42. Saletti, P.G., Mowrey, W.B., Liu, W., Li, Q., McCullough, J., Aniceto, R., Lin, I.H., Eklund, M., Casillas-Espinosa, P.M., Ali, I., Santana-Gomez, C., Coles, L., Shultz, S.R., Jones, N., Staba, R., O'Brien, T.J., Moshe, S.L., Agoston, D.V., Galanopoulou, A.S., 2023. Early preclinical plasma protein biomarkers of brain trauma are influenced by early seizures and levetiracetam. Epilepsia Open. 8, 586-608.
43. Schroder, K., Hertzog, P.J., Ravasi, T., Hume, D.A., 2004. Interferon-gamma:an overview of signals, mechanisms and functions. J. Leukoc. Biol. 75, 163-189.
44. Seth, R.B., Sun, L., Ea, C.K., Chen, Z.J., 2005. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell. 122, 669-682.
45. Song, Y., Wan, X., Gao, L., Pan, Y., Xie, W., Wang, H., Guo, J., 2015. Activated PKR inhibits pancreatic beta-cell proliferation through sumoylation-dependent stabilization of P53. Mol. Immunol. 68, 341-349.
46. Takeuchi, O., Akira, S., 2010. Pattern recognition receptors and inflammation. Cell. 140, 805-820.
47. Varadkar, S., Bien, C.G., Kruse, C.A., Jensen, F.E., Bauer, J., Pardo, C.A., Vincent, A., Mathern, G.W., Cross, J.H., 2014. Rasmussen's encephalitis:clinical features, pathobiology, and treatment advances. Lancet Neurol. 13, 195-205.
48. Vazifehkhah, S., Khanizadeh, A.M., Mojarad, T.B., Nikbakht, F., 2020. The possible role of progranulin on anti-inflammatory effects of metformin in temporal lobe epilepsy. J. Chem. Neuroanat. 109, 101849.
49. Wang, Y.S., Liu, D., Wang, X., Luo, Q.L., Ding, L., Fan, D.Y., Cai, Q.L., Tang, C.Y., Yang, W., Guan, Y.G., Li, T.F., Wang, P.G., Luan, G.M., An, J., 2022. Rasmussen's encephalitis is characterized by relatively lower production of IFN-beta and activated cytotoxic T cell upon herpes viruses infection. J. Neuroinflammation. 19, 70.
50. Zsurka, G., Kunz, W.S., 2015. Mitochondrial dysfunction and seizures:the neuronal energy crisis. Lancet Neurol. 14, 956-966.
Proportional views
Electronic Supplementary Material

10.1016j.virs.2024.01.002-ESM.docx