1887

Abstract

Tick-borne encephalitis (TBE), a disease caused by tick-borne encephalitis virus (TBEV), represents the most important flaviviral neural infection in Europe and north-eastern Asia. In the central nervous system (CNS), neurons are the primary target for TBEV infection; however, infection of non-neuronal CNS cells, such as astrocytes, is not well understood. In this study, we investigated the interaction between TBEV and primary human astrocytes. We report for the first time, to the best of our knowledge, that primary human astrocytes are sensitive to TBEV infection, although the infection did not affect their viability. The infection induced a marked increase in the expression of glial fibrillary acidic protein, a marker of astrocyte activation. In addition, expression of matrix metalloproteinase 9 and several key pro-inflammatory cytokines/chemokines (e.g. tumour necrosis factor α, interferon α, interleukin (IL)-1β, IL-6, IL-8, interferon γ-induced protein 10, macrophage inflammatory protein, but not monocyte chemotactic protein 1) was upregulated. Moreover, we present a detailed description of morphological changes in TBEV-infected cells, as investigated using three-dimensional electron tomography. Several novel ultrastructural changes were observed, including the formation of unique tubule-like structures of 17.9 ±0.15 nm diameter with associated viral particles and/or virus-induced vesicles and located in the rough endoplasmic reticulum of the TBEV-infected cells. This is the first demonstration that TBEV infection activates primary human astrocytes. The infected astrocytes might be a potential source of pro-inflammatory cytokines in the TBEV-infected brain, and might contribute to the TBEV-induced neurotoxicity and blood–brain barrier breakdown that occurs during TBE. The neuropathological significance of our observations is also discussed.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.068411-0
2014-11-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/jgv/95/11/2411.html?itemId=/content/journal/jgv/10.1099/vir.0.068411-0&mimeType=html&fmt=ahah

References

  1. Atrasheuskaya A. V., Fredeking T. M., Ignatyev G. M. 2003; Changes in immune parameters and their correction in human cases of tick-borne encephalitis. Clin Exp Immunol 131:148–154 [View Article][PubMed]
    [Google Scholar]
  2. Balsitis S. J., Coloma J., Castro G., Alava A., Flores D., McKerrow J. H., Beatty P. R., Harris E. 2009; Tropism of dengue virus in mice and humans defined by viral nonstructural protein 3-specific immunostaining. Am J Trop Med Hyg 80:416–424[PubMed]
    [Google Scholar]
  3. Bhowmick S., Duseja R., Das S., Appaiahgiri M. B., Vrati S., Basu A. 2007; Induction of IP-10 (CXCL10) in astrocytes following Japanese encephalitis. Neurosci Lett 414:45–50 [View Article][PubMed]
    [Google Scholar]
  4. Brabers N. A., Nottet H. S. 2006; Role of the pro-inflammatory cytokines TNF-α and IL-1β in HIV-associated dementia. Eur J Clin Invest 36:447–458 [View Article][PubMed]
    [Google Scholar]
  5. Brodie C., Weizman N., Katzoff A., Lustig S., Kobiler D. 1997; Astrocyte activation by Sindbis virus: expression of GFAP, cytokines, and adhesion molecules. Glia 19:275–285 [View Article][PubMed]
    [Google Scholar]
  6. Chen C. J., Liao S. L., Kuo M. D., Wang Y. M. 2000; Astrocytic alteration induced by Japanese encephalitis virus infection. Neuroreport 11:1933–1937 [View Article][PubMed]
    [Google Scholar]
  7. Chen C. J., Chen J. H., Chen S. Y., Liao S. L., Raung S. L. 2004; Upregulation of RANTES gene expression in neuroglia by Japanese encephalitis virus infection. J Virol 78:12107–12119 [View Article][PubMed]
    [Google Scholar]
  8. de Araújo J. M., Schatzmayr H. G., de Filippis A. M., Dos Santos F. B., Cardoso M. A., Britto C., Coelho J. M., Nogueira R. M. 2009; A retrospective survey of dengue virus infection in fatal cases from an epidemic in Brazil. J Virol Methods 155:34–38 [View Article][PubMed]
    [Google Scholar]
  9. De Madrid A. T., Porterfield J. S. 1969; A simple micro-culture method for the study of group B arboviruses. Bull World Health Organ 40:113–121[PubMed]
    [Google Scholar]
  10. del Zoppo G. J. 2010; The neurovascular unit, matrix proteases, and innate inflammation. Ann N Y Acad Sci 1207:46–49 [View Article][PubMed]
    [Google Scholar]
  11. Desai A., Shankar S. K., Ravi V., Chandramuki A., Gourie-Devi M. 1995; Japanese encephalitis virus antigen in the human brain and its topographic distribution. Acta Neuropathol 89:368–373 [View Article][PubMed]
    [Google Scholar]
  12. Diniz J. A., Da Rosa A. P., Guzman H., Xu F., Xiao S. Y., Popov V. L., Vasconcelos P. F., Tesh R. B. 2006; West Nile virus infection of primary mouse neuronal and neuroglial cells: the role of astrocytes in chronic infection. Am J Trop Med Hyg 75:691–696[PubMed]
    [Google Scholar]
  13. Erickson M. A., Dohi K., Banks W. A. 2012; Neuroinflammation: a common pathway in CNS diseases as mediated at the blood–brain barrier. Neuroimmunomodulation 19:121–130 [View Article][PubMed]
    [Google Scholar]
  14. Fan Y., Zou W., Green L. A., Kim B. O., He J. J. 2011; Activation of Egr-1 expression in astrocytes by HIV-1 Tat: new insights into astrocyte-mediated Tat neurotoxicity. J Neuroimmune Pharmacol 6:121–129 [View Article][PubMed]
    [Google Scholar]
  15. Gelpi E., Preusser M., Garzuly F., Holzmann H., Heinz F. X., Budka H. 2005; Visualization of Central European tick-borne encephalitis infection in fatal human cases. J Neuropathol Exp Neurol 64:506–512[PubMed]
    [Google Scholar]
  16. Gelpi E., Preusser M., Laggner U., Garzuly F., Holzmann H., Heinz F. X., Budka H. 2006; Inflammatory response in human tick-borne encephalitis: analysis of postmortem brain tissue. J Neurovirol 12:322–327 [View Article][PubMed]
    [Google Scholar]
  17. German A. C., Myint K. S., Mai N. T., Pomeroy I., Phu N. H., Tzartos J., Winter P., Collett J., Farrar J.other authors 2006; A preliminary neuropathological study of Japanese encephalitis in humans and a mouse model. Trans R Soc Trop Med Hyg 100:1135–1145 [View Article][PubMed]
    [Google Scholar]
  18. Ghoshal A., Das S., Ghosh S., Mishra M. K., Sharma V., Koli P., Sen E., Basu A. 2007; Proinflammatory mediators released by activated microglia induces neuronal death in Japanese encephalitis. Glia 55:483–496 [View Article][PubMed]
    [Google Scholar]
  19. Gillespie L. K., Hoenen A., Morgan G., Mackenzie J. M. 2010; The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol 84:10438–10447 [View Article][PubMed]
    [Google Scholar]
  20. Gritsun T. S., Frolova T. V., Zhankov A. I., Armesto M., Turner S. L., Frolova M. P., Pogodina V. V., Lashkevich V. A., Gould E. A. 2003; Characterization of a Siberian virus isolated from a patient with progressive chronic tick-borne encephalitis. J Virol 77:25–36 [View Article][PubMed]
    [Google Scholar]
  21. Haglund M., Günther G. 2003; Tick-borne encephalitis–pathogenesis, clinical course and long-term follow-up. Vaccine 21:Suppl. 1S11–S18 [View Article][PubMed]
    [Google Scholar]
  22. Hirano M., Yoshii K., Sakai M., Hasebe R., Ichii O., Kariwa H. 2014; Tick-borne flaviviruses alter membrane structure and replicate in dendrites of primary mouse neuronal cultures. J Gen Virol 95:849–861 [View Article][PubMed]
    [Google Scholar]
  23. Hussmann K. L., Fredericksen B. L. 2014; Differential induction of CCL5 by pathogenic and non-pathogenic strains of West Nile virus in brain endothelial cells and astrocytes. J Gen Virol 95:862–867 [View Article][PubMed]
    [Google Scholar]
  24. Hussmann K. L., Samuel M. A., Kim K. S., Diamond M. S., Fredericksen B. L. 2013; Differential replication of pathogenic and nonpathogenic strains of West Nile virus within astrocytes. J Virol 87:2814–2822 [View Article][PubMed]
    [Google Scholar]
  25. Imbert J. L., Guevara P., Ramos-Castañeda J., Ramos C., Sotelo J. 1994; Dengue virus infects mouse cultured neurons but not astrocytes. J Med Virol 42:228–233 [View Article][PubMed]
    [Google Scholar]
  26. Kang X., Li Y., Wei J., Zhang Y., Bian C., Wang K., Wu X., Hu Y., Li J., Yang Y. 2013; Elevation of matrix metalloproteinase-9 level in cerebrospinal fluid of tick-borne encephalitis patients is associated with IgG extravassation and disease severity. PLoS ONE 8:e77427 [View Article][PubMed]
    [Google Scholar]
  27. Klein R. S., Lin E., Zhang B., Luster A. D., Tollett J., Samuel M. A., Engle M., Diamond M. S. 2005; Neuronal CXCL10 directs CD8+ T-cell recruitment and control of West Nile virus encephalitis. J Virol 79:11457–11466 [View Article][PubMed]
    [Google Scholar]
  28. Környey S. 1978; Contribution to the histology of tick-borne encephalitis. Acta Neuropathol 43:179–183 [View Article][PubMed]
    [Google Scholar]
  29. Kožuch O., Mayer V. 1975; Pig kidney epithelial (PS) cells: a perfect tool for the study of flaviviruses and some other arboviruses. Acta Virol 19:498[PubMed]
    [Google Scholar]
  30. Kremer J. R., Mastronarde D. N., McIntosh J. R. 1996; Computer visualization of three-dimensional image data using IMOD. J Struct Biol 116:71–76 [View Article][PubMed]
    [Google Scholar]
  31. Kumar M., Verma S., Nerurkar V. R. 2010; Pro-inflammatory cytokines derived from West Nile virus (WNV)-infected SK-N-SH cells mediate neuroinflammatory markers and neuronal death. J Neuroinflammation 7:73 [View Article][PubMed]
    [Google Scholar]
  32. Lepej S. Z., Misić-Majerus L., Jeren T., Rode O. D., Remenar A., Sporec V., Vince A. 2007; Chemokines CXCL10 and CXCL11 in the cerebrospinal fluid of patients with tick-borne encephalitis. Acta Neurol Scand 115:109–114 [View Article][PubMed]
    [Google Scholar]
  33. Letournel-Boulland M. L., Fages C., Rolland B., Tardy M. 1994; Lipopolysaccharides (LPS), up-regulate the IL-1-mRNA and down-regulate the glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS)-mRNAs in astroglial primary cultures. Eur Cytokine Netw 5:51–56[PubMed]
    [Google Scholar]
  34. Livak K. J., Schmittgen T. D. 2001; Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25:402–408 [View Article][PubMed]
    [Google Scholar]
  35. Lorenz I. C., Kartenbeck J., Mezzacasa A., Allison S. L., Heinz F. X., Helenius A. 2003; Intracellular assembly and secretion of recombinant subviral particles from tick-borne encephalitis virus. J Virol 77:4370–4382 [View Article][PubMed]
    [Google Scholar]
  36. Mansfield K. L., Johnson N., Phipps L. P., Stephenson J. R., Fooks A. R., Solomon T. 2009; Tick-borne encephalitis virus – a review of an emerging zoonosis. J Gen Virol 90:1781–1794 [View Article][PubMed]
    [Google Scholar]
  37. Mastronarde D. N. 2005; Automated electron microscope tomography using robust prediction of specimen movements. J Struct Biol 152:36–51 [View Article][PubMed]
    [Google Scholar]
  38. McColl B. W., Rothwell N. J., Allan S. M. 2008; Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice. J Neurosci 28:9451–9462 [View Article][PubMed]
    [Google Scholar]
  39. Miorin L., Romero-Brey I., Maiuri P., Hoppe S., Krijnse-Locker J., Bartenschlager R., Marcello A. 2013; Three-dimensional architecture of tick-borne encephalitis virus replication sites and trafficking of the replicated RNA. J Virol 87:6469–6481 [View Article][PubMed]
    [Google Scholar]
  40. Montgomery D. L. 1994; Astrocytes: form, functions, and roles in disease. Vet Pathol 31:145–167 [View Article][PubMed]
    [Google Scholar]
  41. Nedergaard M., Ransom B., Goldman S. A. 2003; New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci 26:523–530 [View Article][PubMed]
    [Google Scholar]
  42. Nogueira R. M., Filippis A. M., Coelho J. M., Sequeira P. C., Schatzmayr H. G., Paiva F. G., Ramos A. M., Miagostovich M. P. 2002; Dengue virus infection of the central nervous system (CNS): a case report from Brazil. Southeast Asian J Trop Med Public Health 33:68–71[PubMed]
    [Google Scholar]
  43. Offerdahl D. K., Dorward D. W., Hansen B. T., Bloom M. E. 2012; A three-dimensional comparison of tick-borne flavivirus infection in mammalian and tick cell lines. PLoS ONE 7:e47912 [View Article][PubMed]
    [Google Scholar]
  44. Ojeda D., López-Costa J. J., Sede M., López E. M., Berria M. I., Quarleri J. 2014; Increased in vitro glial fibrillary acidic protein expression, telomerase activity, and telomere length after productive human immunodeficiency virus-1 infection in murine astrocytes. J Neurosci Res 92:267–274 [View Article][PubMed]
    [Google Scholar]
  45. Overby A. K., Popov V. L., Niedrig M., Weber F. 2010; Tick-borne encephalitis virus delays interferon induction and hides its double-stranded RNA in intracellular membrane vesicles. J Virol 84:8470–8483 [View Article][PubMed]
    [Google Scholar]
  46. Palus M., Vojtíšková J., Salát J., Kopecký J., Grubhoffer L., Lipoldová M., Demant P., Růžek D. 2013; Mice with different susceptibility to tick-borne encephalitis virus infection show selective neutralizing antibody response and inflammatory reaction in the central nervous system. J Neuroinflammation 10:77 [View Article][PubMed]
    [Google Scholar]
  47. Palus M., Zampachová E., Elsterová J., Růžek D. 2014; Serum matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 levels in patients with tick-borne encephalitis. J Infect 68:165–169 [View Article][PubMed]
    [Google Scholar]
  48. Pekny M., Wilhelmsson U., Pekna M. 2014; The dual role of astrocyte activation and reactive gliosis. Neurosci Lett 565:30–38 [View Article][PubMed]
    [Google Scholar]
  49. Potokar M., Korva M., Jorgačevski J., Avšič-Županc T., Zorec R. 2014; Tick-borne encephalitis virus infects rat astrocytes but does not affect their viability. PLoS ONE 9:e86219 [View Article][PubMed]
    [Google Scholar]
  50. Pozner R. G., Collado S., Jaquenod de Giusti C., Ure A. E., Biedma M. E., Romanowski V., Schattner M., Gómez R. M. 2008; Astrocyte response to Junín virus infection. Neurosci Lett 445:31–35 [View Article][PubMed]
    [Google Scholar]
  51. Ramesh G., MacLean A. G., Philipp M. T. 2013; Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration, and neuropathic pain. Mediators Inflamm 2013:480739 [View Article][PubMed]
    [Google Scholar]
  52. Réaux-Le Goazigo A., Van Steenwinckel J., Rostène W., Mélik Parsadaniantz S. 2013; Current status of chemokines in the adult CNS. Prog Neurobiol 104:67–92 [View Article][PubMed]
    [Google Scholar]
  53. Rey F. A., Heinz F. X., Mandl C., Kunz C., Harrison S. C. 1995; The envelope glycoprotein from tick-borne encephalitis virus at 2 Å resolution. Nature 375:291–298 [View Article][PubMed]
    [Google Scholar]
  54. Růzek D., Salát J., Palus M., Gritsun T. S., Gould E. A., Dyková I., Skallová A., Jelínek J., Kopecký J., Grubhoffer L. 2009a; CD8+ T-cells mediate immunopathology in tick-borne encephalitis. Virology 384:1–6 [View Article][PubMed]
    [Google Scholar]
  55. Růzek D., Vancová M., Tesarová M., Ahantarig A., Kopecký J., Grubhoffer L. 2009b; Morphological changes in human neural cells following tick-borne encephalitis virus infection. J Gen Virol 90:1649–1658 [View Article][PubMed]
    [Google Scholar]
  56. Růžek D., Dobler G., Donoso Mantke O. 2010; Tick-borne encephalitis: pathogenesis and clinical implications. Travel Med Infect Dis 8:223–232 [View Article][PubMed]
    [Google Scholar]
  57. Růžek D., Salát J., Singh S. K., Kopecký J. 2011; Breakdown of the blood-brain barrier during tick-borne encephalitis in mice is not dependent on CD8+ T-cells. PLoS ONE 6:e20472 [View Article][PubMed]
    [Google Scholar]
  58. Sasseville V. G., Smith M. M., Mackay C. R., Pauley D. R., Mansfield K. G., Ringler D. J., Lackner A. A. 1996; Chemokine expression in simian immunodeficiency virus-induced AIDS encephalitis. Am J Pathol 149:1459–1467[PubMed]
    [Google Scholar]
  59. Sips G. J., Wilschut J., Smit J. M. 2012; Neuroinvasive flavivirus infections. Rev Med Virol 22:69–87 [View Article][PubMed]
    [Google Scholar]
  60. Stanimirovic D. B., Friedman A. 2012; Pathophysiology of the neurovascular unit: disease cause or consequence?. J Cereb Blood Flow Metab 32:1207–1221 [View Article][PubMed]
    [Google Scholar]
  61. Sui Y., Potula R., Dhillon N., Pinson D., Li S., Nath A., Anderson C., Turchan J., Kolson D.other authors 2004; Neuronal apoptosis is mediated by CXCL10 overexpression in simian human immunodeficiency virus encephalitis. Am J Pathol 164:1557–1566 [View Article][PubMed]
    [Google Scholar]
  62. Sui Y., Stehno-Bittel L., Li S., Loganathan R., Dhillon N. K., Pinson D., Nath A., Kolson D., Narayan O., Buch S. 2006; CXCL10-induced cell death in neurons: role of calcium dysregulation. Eur J Neurosci 23:957–964 [View Article][PubMed]
    [Google Scholar]
  63. Verma S., Kumar M., Nerurkar V. R. 2011; Cyclooxygenase-2 inhibitor blocks the production of West Nile virus-induced neuroinflammatory markers in astrocytes. J Gen Virol 92:507–515 [View Article][PubMed]
    [Google Scholar]
  64. Watanabe C., Kawashima H., Takekuma K., Hoshika A., Watanabe Y. 2008; Increased nitric oxide production and GFAP expression in the brains of influenza A/NWS virus infected mice. Neurochem Res 33:1017–1023 [View Article][PubMed]
    [Google Scholar]
  65. Welsch S., Miller S., Romero-Brey I., Merz A., Bleck C. K., Walther P., Fuller S. D., Antony C., Krijnse-Locker J., Bartenschlager R. 2009; Composition and three-dimensional architecture of the dengue virus replication and assembly sites. Cell Host Microbe 5:365–375 [View Article][PubMed]
    [Google Scholar]
  66. Westmoreland S. V., Rottman J. B., Williams K. C., Lackner A. A., Sasseville V. G. 1998; Chemokine receptor expression on resident and inflammatory cells in the brain of macaques with simian immunodeficiency virus encephalitis. Am J Pathol 152:659–665[PubMed]
    [Google Scholar]
  67. Yang C. M., Lin C. C., Lee I. T., Lin Y. H., Yang C. M., Chen W. J., Jou M. J., Hsiao L. D. 2012; Japanese encephalitis virus induces matrix metalloproteinase-9 expression via a ROS/c-Src/PDGFR/PI3K/Akt/MAPKs-dependent AP-1 pathway in rat brain astrocytes. J Neuroinflammation 9:12 [View Article][PubMed]
    [Google Scholar]
  68. Yao Y., Tsirka S. E. 2014; Monocyte chemoattractant protein-1 and the blood–brain barrier. Cell Mol Life Sci 71:683–697 [View Article][PubMed]
    [Google Scholar]
  69. Zajkowska J., Moniuszko-Malinowska A., Pancewicz S. A., Muszyńska-Mazur A., Kondrusik M., Grygorczuk S., Swierzbińska-Pijanowska R., Dunaj J., Czupryna P. 2011; Evaluation of CXCL10, CXCL11, CXCL12 and CXCL13 chemokines in serum and cerebrospinal fluid in patients with tick borne encephalitis (TBE). Adv Med Sci 56:311–317 [View Article][PubMed]
    [Google Scholar]
  70. Zhou B. Y., Liu Y., Kim Bo., Xiao Y., He J. J. 2004; Astrocyte activation and dysfunction and neuron death by HIV-1 Tat expression in astrocytes. Mol Cell Neurosci 27:296–305 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.068411-0
Loading
/content/journal/jgv/10.1099/vir.0.068411-0
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error