Serving the Society Since 1986
Advanced Search
Volume 38 Issue 1
February 2023
    Citation: Erlin Wang, Xinwei Huang, Yunshuang Ye, Shiqing Zou, Guijun Chen, Liping Yang, Nigel W. Fraser, Fukai Bao, Jumin Zhou, Xia Cao. Persistent inflammation and neuronal loss in the mouse brain induced by a modified form of attenuated herpes simplex virus type I .VIROLOGICA SINICA, 2023, 38(1) : 108-118.  http://dx.doi.org/10.1016/j.virs.2022.11.008
    shu

    Persistent inflammation and neuronal loss in the mouse brain induced by a modified form of attenuated herpes simplex virus type I

    • a. Key Laboratory of Second Affiliated Hospital of Kunming Medical University, Kunming, 650000, China;

    • b. Key Laboratory of Animal Models and Human Disease Mechanism of the Chinese Academy of Science/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, 650223, China;

    • c. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, China;

    • d. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA;

    • e. Department of Biology and Immunology, Kunming Medical University, Kunming, 650101, China;

    • f. KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming, 650223, China

    • Herpes simplex virus-1 (HSV-1) is a widespread neurotropic virus that can reach the brain and cause a rare but acute herpes simplex encephalitis (HSE) with a high mortality rate. Most patients present with changes in neurological and behavioral status, and survivors suffer long-term neurological sequelae. To date, the pathogenesis leading to brain damage is still not well understood. HSV-1 induced encephalitis in the central nervous system (CNS) in animals are usually very diffuse and progressing rapidly, and mostly fatal, making the analysis difficult. Here, we established a mouse model of HSE via intracerebral inoculation of modified version of neural-attenuated strains of HSV-1 (deletion of ICP34.5 and inserting a strong promoter into the latency-associated transcript region), in which the LMR-αΔpA strain initiated moderate productive infection, leading to strong host immune and inflammatory response characterized by persistent microglia activation. This viral replication activity and prolonged inflammatory response activated signaling pathways in neuronal damage, amyloidosis, Alzheimer's disease, and neurodegeneration, eventually leading to neuronal loss and behavioral changes characterized by hypokinesia. Our study reveals detailed pathogenic processes and persistent inflammatory responses in the CNS and provides a controlled, mild and non-lethal HSE model for studying long-term neuronal injury and increased risk of neurodegenerative diseases due to HSV-1 infection.
    • 加载中

    • Electronic Supplementary Material

      10.1016j.virs.2022.11.008-ESM1.pdf
      10.1016j.virs.2022.11.008-ESM2.pdf
      10.1016j.virs.2022.11.008-ESM3.pdf
      10.1016j.virs.2022.11.008-ESM4.pdf
      10.1016j.virs.2022.11.008-ESM5.docx

      1. Alexander DE, Leib DA. 2008. Xenophagy in herpes simplex virus replication and pathogenesis. Autophagy, 4:101-103.

      2. Armien AG, Hu S, Little MR, Robinson N, Lokensgard JR, Low WC, Cheeran MC. 2010. Chronic cortical and subcortical pathology with associated neurological deficits ensuing experimental herpes encephalitis. Brain Pathol, 20:738-750.

      3. Asai M, Hattori C, Szabo B, Sasagawa N, Maruyama K, Tanuma S, Ishiura S. 2003. Putative function of adam9, adam10, and adam17 as app alpha-secretase. Biochem Biophys Res Commun, 301:231-235.

      4. Barker KR, Sarafino-Wani R, Khanom A, Griffiths PD, Jacobs MG, Webster DP. 2014. Encephalitis in an immunocompetent man. J Clin Virol, 59:1-3.

      5. Bohmwald K, Andrade CA, Galvez NMS, Mora VP, Munoz JT, Kalergis AM. 2021. The causes and long-term consequences of viral encephalitis. Front Cell Neurosci, 15:755875.

      6. Cassady KA, Gross M, Roizman B. 1998. The herpes simplex virus us11 protein effectively compensates for the gamma1(34.5) gene if present before activation of protein kinase r by precluding its phosphorylation and that of the alpha subunit of eukaryotic translation initiation factor 2. J Virol, 72:8620-8626.

      7. Chhatbar C, Prinz M. 2021. The roles of microglia in viral encephalitis:From sensome to therapeutic targeting. Cell Mol Immunol, 18:250-258.

      8. Chou J, Kern ER, Whitley RJ, Roizman B. 1990. Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nonessential for growth in culture. Science, 250:1262-1266.

      9. De Chiara G, Piacentini R, Fabiani M, Mastrodonato A, Marcocci ME, Limongi D, Napoletani G, Protto V, Coluccio P, Celestino I, Li Puma DD, Grassi C, Palamara AT. 2019. Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice. PLoS Pathog, 15:e1007617.

      10. Esiri MM. 1982. Herpes simplex encephalitis. An immunohistological study of the distribution of viral antigen within the brain. J Neurol Sci, 54:209-226.

      11. Ezzat K, Pernemalm M, Palsson S, Roberts TC, Jarver P, Dondalska A, Bestas B, Sobkowiak MJ, Levanen B, Skold M, Thompson EA, Saher O, Kari OK, Lajunen T, Sverremark Ekstrom E, Nilsson C, Ishchenko Y, Malm T, Wood MJA, Power UF, Masich S, Linden A, Sandberg JK, Lehtio J, Spetz AL, El Andaloussi S. 2019. The viral protein corona directs viral pathogenesis and amyloid aggregation. Nat Commun, 10:2331.

      12. Farrell MJ, Dobson AT, Feldman LT. 1991. Herpes simplex virus latency-associated transcript is a stable intron. Proc Natl Acad Sci U S A, 88:790-794.

      13. Gale M, Jr., Katze MG. 1998. Molecular mechanisms of interferon resistance mediated by viral-directed inhibition of pkr, the interferon-induced protein kinase. Pharmacol Ther, 78:29-46.

      14. Getts DR, Terry RL, Getts MT, Muller M, Rana S, Shrestha B, Radford J, Van Rooijen N, Campbell IL, King NJ. 2008. Ly6c+ "inflammatory monocytes" are microglial precursors recruited in a pathogenic manner in west nile virus encephalitis. J Exp Med, 205:2319-2337.

      15. He B, Gross M, Roizman B. 1998. The gamma134.5 protein of herpes simplex virus 1 has the structural and functional attributes of a protein phosphatase 1 regulatory subunit and is present in a high molecular weight complex with the enzyme in infected cells. J Biol Chem, 273:20737-20743.

      16. Huang X, Li X, Yang L, Wang P, Yan J, Nie Z, Gao Y, Li Z, Wen J, Cao X. 2022. Construction and optimization of herpes simplex virus vectors for central nervous system gene delivery based on crispr/cas9-mediated genome editing. Curr Gene Ther, 22:66-77.

      17. Huang Z, Wu SQ, Liang Y, Zhou X, Chen W, Li L, Wu J, Zhuang Q, Chen C, Li J, Zhong CQ, Xia W, Zhou R, Zheng C, Han J. 2015. Rip1/rip3 binding to hsv-1 icp6 initiates necroptosis to restrict virus propagation in mice. Cell Host Microbe, 17:229-242.

      18. Kastrukoff L, Hamada T, Schumacher U, Long C, Doherty PC, Koprowski H. 1982. Central nervous system infection and immune response in mice inoculated into the lip with herpes simplex virus type 1. J Neuroimmunol, 2:295-305.

      19. Klein RS, Garber C, Howard N. 2017. Infectious immunity in the central nervous system and brain function. Nat Immunol, 18:132-141.

      20. Kollias CM, Huneke RB, Wigdahl B, Jennings SR. 2015. Animal models of herpes simplex virus immunity and pathogenesis. J Neurovirol, 21:8-23.

      21. Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, Damko E, Moquin D, Walz T, McDermott A, Chan FK, Wu H. 2012. The rip1/rip3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell, 150:339-350.

      22. Li L, Li Z, Wang E, Yang R, Xiao Y, Han H, Lang F, Li X, Xia Y, Gao F, Li Q, Fraser NW, Zhou J. 2015. Herpes simplex virus 1 infection of tree shrews differs from that of mice in the severity of acute infection and viral transcription in the peripheral nervous system. J Virol, 90:790-804.

      23. Liao Y, Smyth GK, Shi W. 2014. Featurecounts:An efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics, 30:923-930.

      24. Love MI, Huber W, Anders S. 2014. Moderated estimation of fold change and dispersion for rna-seq data with deseq2. Genome Biol, 15:550.

      25. Lussignol M, Queval C, Bernet-Camard MF, Cotte-Laffitte J, Beau I, Codogno P, Esclatine A. 2013. The herpes simplex virus 1 us11 protein inhibits autophagy through its interaction with the protein kinase pkr. J Virol, 87:859-871.

      26. MacLean AR, ul-Fareed M, Robertson L, Harland J, Brown SM. 1991. Herpes simplex virus type 1 deletion variants 1714 and 1716 pinpoint neurovirulence-related sequences in glasgow strain 17+ between immediate early gene 1 and the ‘a’ sequence. J Gen Virol, 72 (Pt 3):631-639.

      27. Mancini M, Vidal SM. 2018. Insights into the pathogenesis of herpes simplex encephalitis from mouse models. Mamm Genome, 29:425-445.

      28. McGrath N, Anderson NE, Croxson MC, Powell KF. 1997. Herpes simplex encephalitis treated with acyclovir:Diagnosis and long term outcome. J Neurol Neurosurg Psychiatry, 63:321-326.

      29. McKie EA, Brown SM, MacLean AR, Graham DI. 1998. Histopathological responses in the cns following inoculation with a non-neurovirulent mutant (1716) of herpes simplex virus type 1 (hsv 1):Relevance for gene and cancer therapy. Neuropathol Appl Neurobiol, 24:367-372.

      30. McKie EA, MacLean AR, Lewis AD, Cruickshank G, Rampling R, Barnett SC, Kennedy PG, Brown SM. 1996. Selective in vitro replication of herpes simplex virus type 1 (hsv-1) icp34.5 null mutants in primary human cns tumours--evaluation of a potentially effective clinical therapy. Br J Cancer, 74:745-752.

      31. Orlando JS, Astor TL, Rundle SA, Schaffer PA. 2006. The products of the herpes simplex virus type 1 immediate-early us1/us1.5 genes downregulate levels of s-phase-specific cyclins and facilitate virus replication in s-phase vero cells. J Virol, 80:4005-4016.

      32. Orvedahl A, Alexander D, Talloczy Z, Sun Q, Wei Y, Zhang W, Burns D, Leib DA, Levine B. 2007. Hsv-1 icp34.5 confers neurovirulence by targeting the beclin 1 autophagy protein. Cell Host Microbe, 1:23-35.

      33. Perng GC, Ghiasi H, Slanina SM, Nesburn AB, Wechsler SL. 1996. The spontaneous reactivation function of the herpes simplex virus type 1 lat gene resides completely within the first 1.5 kilobases of the 8.3-kilobase primary transcript. J Virol, 70:976-984.

      34. Raudvere U, Kolberg L, Kuzmin I, Arak T, Adler P, Peterson H, Vilo J. 2019. G:Profiler:A web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res, 47:W191-W198.

      35. Robertson LM, MacLean AR, Brown SM. 1992. Peripheral replication and latency reactivation kinetics of the non-neurovirulent herpes simplex virus type 1 variant 1716. J Gen Virol, 73 ( Pt 4):967-970.

      36. Sandri-Goldin RM. 1998. Icp27 mediates hsv rna export by shuttling through a leucine-rich nuclear export signal and binding viral intronless rnas through an rgg motif. Genes Dev, 12:868-879.

      37. Sehl-Ewert J, Schwaiger T, Schafer A, Holper JE, Klupp BG, Teifke JP, Blohm U, Mettenleiter TC. 2022. Clinical, neuropathological, and immunological short- and long-term feature of a mouse model mimicking human herpes virus encephalitis. Brain Pathol, 32:e13031.

      38. Sehl J, Holper JE, Klupp BG, Baumbach C, Teifke JP, Mettenleiter TC. 2020. An improved animal model for herpesvirus encephalitis in humans. PLoS Pathog, 16:e1008445.

      39. Sharma K, Schmitt S, Bergner CG, Tyanova S, Kannaiyan N, Manrique-Hoyos N, Kongi K, Cantuti L, Hanisch UK, Philips MA, Rossner MJ, Mann M, Simons M. 2015. Cell type- and brain region-resolved mouse brain proteome. Nat Neurosci, 18:1819-1831.

      40. Smialowski A. 1989. Chronic administration of sch 23390 enhances spontaneous searching and locomotor activity of rats. An open field study. Behav Brain Res, 35:41-44.

      41. Stroop WG, Rock DL, Fraser NW. 1984. Localization of herpes simplex virus in the trigeminal and olfactory systems of the mouse central nervous system during acute and latent infections by in situ hybridization. Lab Invest, 51:27-38.

      42. Talloczy Z, Virgin HWt, Levine B. 2006. Pkr-dependent autophagic degradation of herpes simplex virus type 1. Autophagy, 2:24-29.

      43. Tyler KL. 2004. Herpes simplex virus infections of the central nervous system:Encephalitis and meningitis, including mollaret's. Herpes, 11 Suppl 2:57A-64A.

      44. Tyler KL. 2018. Acute viral encephalitis. N Engl J Med, 379:557-566.

      45. Tzeng NS, Chung CH, Lin FH, Chiang CP, Yeh CB, Huang SY, Lu RB, Chang HA, Kao YC, Yeh HW, Chiang WS, Chou YC, Tsao CH, Wu YF, Chien WC. 2018. Anti-herpetic medications and reduced risk of dementia in patients with herpes simplex virus infections-a nationwide, population-based cohort study in taiwan. Neurotherapeutics, 15:417-429.

      46. Waisner H, Kalamvoki M. 2019. 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. J Virol, 93.

      47. Wang E, Ye Y, Zhang K, Yang J, Gong D, Zhang J, Hong R, Zhang H, Li L, Chen G, Yang L, Liu J, Cao H, Du T, Fraser NW, Cheng L, Cao X, Zhou J. 2020. Longitudinal transcriptomic characterization of viral genes in hsv-1 infected tree shrew trigeminal ganglia. Virol J, 17:95.

      48. Wang X, Li Y, Liu S, Yu X, Li L, Shi C, He W, Li J, Xu L, Hu Z, Yu L, Yang Z, Chen Q, Ge L, Zhang Z, Zhou B, Jiang X, Chen S, He S. 2014. Direct activation of rip3/mlkl-dependent necrosis by herpes simplex virus 1 (hsv-1) protein icp6 triggers host antiviral defense. Proc Natl Acad Sci U S A, 111:15438-15443.

      49. Wheeler DL, Sariol A, Meyerholz DK, Perlman S. 2018. Microglia are required for protection against lethal coronavirus encephalitis in mice. J Clin Invest, 128:931-943.

      50. Whitley RJ. 1991. Herpes simplex virus infections of the central nervous system. Encephalitis and neonatal herpes. Drugs, 42:406-427.

      51. Whitley RJ, Kern ER, Chatterjee S, Chou J, Roizman B. 1993. Replication, establishment of latency, and induced reactivation of herpes simplex virus gamma 1 34.5 deletion mutants in rodent models. J Clin Invest, 91:2837-2843.

      52. Zhang X, Lan Y, Xu J, Quan F, Zhao E, Deng C, Luo T, Xu L, Liao G, Yan M, Ping Y, Li F, Shi A, Bai J, Zhao T, Li X, Xiao Y. 2019. Cellmarker:A manually curated resource of cell markers in human and mouse. Nucleic Acids Res, 47:D721-D728.

      53. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, Deng S, Liddelow SA, Zhang C, Daneman R, Maniatis T, Barres BA, Wu JQ. 2014. An rna-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci, 34:11929-11947.

    • 加载中
    PDF

    Article Metrics

    Article views(2422) PDF downloads(11) Cited by()

    Related
    Proportional views

      Persistent inflammation and neuronal loss in the mouse brain induced by a modified form of attenuated herpes simplex virus type I

        Corresponding author: Jumin Zhou, zhoujm@mail.kiz.ac.cn
        Corresponding author: Xia Cao, caoxia@kmmu.edu.cn
      • a. Key Laboratory of Second Affiliated Hospital of Kunming Medical University, Kunming, 650000, China;
      • b. Key Laboratory of Animal Models and Human Disease Mechanism of the Chinese Academy of Science/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, 650223, China;
      • c. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, China;
      • d. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA;
      • e. Department of Biology and Immunology, Kunming Medical University, Kunming, 650101, China;
      • f. KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming, 650223, China
      • Received Date: 19 July 2022
      • Accepted Date: 21 November 2022

      Abstract: Herpes simplex virus-1 (HSV-1) is a widespread neurotropic virus that can reach the brain and cause a rare but acute herpes simplex encephalitis (HSE) with a high mortality rate. Most patients present with changes in neurological and behavioral status, and survivors suffer long-term neurological sequelae. To date, the pathogenesis leading to brain damage is still not well understood. HSV-1 induced encephalitis in the central nervous system (CNS) in animals are usually very diffuse and progressing rapidly, and mostly fatal, making the analysis difficult. Here, we established a mouse model of HSE via intracerebral inoculation of modified version of neural-attenuated strains of HSV-1 (deletion of ICP34.5 and inserting a strong promoter into the latency-associated transcript region), in which the LMR-αΔpA strain initiated moderate productive infection, leading to strong host immune and inflammatory response characterized by persistent microglia activation. This viral replication activity and prolonged inflammatory response activated signaling pathways in neuronal damage, amyloidosis, Alzheimer's disease, and neurodegeneration, eventually leading to neuronal loss and behavioral changes characterized by hypokinesia. Our study reveals detailed pathogenic processes and persistent inflammatory responses in the CNS and provides a controlled, mild and non-lethal HSE model for studying long-term neuronal injury and increased risk of neurodegenerative diseases due to HSV-1 infection.

        HTML

      Reference (53) Relative (20)

      目录

      This journal is a member of, and subscribes to the principles of, the Committee on Publication Ethics (COPE)

      鄂ICP备05001977号

         

      鄂公网安备 42010602003674号

      Copyright © 2019 Virologica Sinica. All rights reserved

      /

      DownLoad:  Full-Size Img  PowerPoint
      Return
      Return