1887

Abstract

West Nile virus (WNV) encephalitis is characterized by neuroinflammation, neuronal loss and blood–brain barrier (BBB) disruption. However, the mechanisms associated with the BBB disruption are unclear. Complex interactions between the tight junction proteins (TJP) and the adherens junction proteins (AJP) of the brain microvascular endothelial cells are responsible for maintaining the BBB integrity. Herein, we characterized the relationship between the BBB disruption and expression kinetics of key TJP, AJP and matrix metalloproteinases (MMPs) in the mice brain. A dramatic increase in the BBB permeability and extravasation of IgG was observed at later time points of the central nervous system (CNS) infection and did not precede virus–CNS entry. WNV-infected mice exhibited significant reduction in the protein levels of the TJP ZO-1, claudin-1, occludin and JAM-A, and AJP β-catenin and vascular endothelial cadherin, which correlated with increased levels of MMP-1, -3 and -9 and infiltrated leukocytes in the brain. Further, intracranial inoculation of WNV also demonstrated increased extravasation of IgG in the brain, suggesting the role of virus replication in the CNS in BBB disruption. These data suggest that altered expression of junction proteins is a pathological event associated with WNV infection and may explain the molecular basis of BBB disruption. We propose that WNV initially enters CNS without altering the BBB integrity and later virus replication in the brain initiates BBB disruption, allowing enhanced infiltration of immune cells and contribute to virus neuroinvasion via the ‘Trojan-horse’ route. These data further implicate roles of multiple MMPs in the BBB disruption and strategies to interrupt this process may influence the WNV disease outcome.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.040899-0
2012-06-01
2020-08-12
Loading full text...

Full text loading...

/deliver/fulltext/jgv/93/6/1193.html?itemId=/content/journal/jgv/10.1099/vir.0.040899-0&mimeType=html&fmt=ahah

References

  1. Abbott N. J.. 2005; Dynamics of CNS barriers: evolution, differentiation, and modulation. Cell Mol Neurobiol25:5–23 [CrossRef][PubMed]
    [Google Scholar]
  2. Afonso P. V., Ozden S., Prevost M. C., Schmitt C., Seilhean D., Weksler B., Couraud P. O., Gessain A., Romero I. A., Ceccaldi P. E.. 2007; Human blood-brain barrier disruption by retroviral-infected lymphocytes: role of myosin light chain kinase in endothelial tight-junction disorganization. J Immunol179:2576–2583[PubMed][CrossRef]
    [Google Scholar]
  3. Arjona A., Foellmer H. G., Town T., Leng L., McDonald C., Wang T., Wong S. J., Montgomery R. R., Fikrig E., Bucala R.. 2007; Abrogation of macrophage migration inhibitory factor decreases West Nile virus lethality by limiting viral neuroinvasion. J Clin Invest117:3059–3066 [CrossRef][PubMed]
    [Google Scholar]
  4. Bazzoni G., Martinez-Estrada O. M., Orsenigo F., Cordenonsi M., Citi S., Dejana E.. 2000; Interaction of junctional adhesion molecule with the tight junction components ZO-1, cingulin, and occludin. J Biol Chem275:20520–20526 [CrossRef][PubMed]
    [Google Scholar]
  5. Boven L. A., Middel J., Verhoef J., De Groot C. J., Nottet H. S.. 2000; Monocyte infiltration is highly associated with loss of the tight junction protein zonula occludens in HIV-1-associated dementia. Neuropathol Appl Neurobiol26:356–360 [CrossRef][PubMed]
    [Google Scholar]
  6. Campbell G. L., Marfin A. A., Lanciotti R. S., Gubler D. J.. 2002; West Nile virus. Lancet Infect Dis2:519–529 [CrossRef][PubMed]
    [Google Scholar]
  7. Cosby S. L., Brankin B.. 1995; Measles virus infection of cerebral endothelial cells and effect on their adhesive properties. Vet Microbiol44:135–139 [CrossRef][PubMed]
    [Google Scholar]
  8. Dallasta L. M., Pisarov L. A., Esplen J. E., Werley J. V., Moses A. V., Nelson J. A., Achim C. L.. 1999; Blood-brain barrier tight junction disruption in human immunodeficiency virus-1 encephalitis. Am J Pathol155:1915–1927 [CrossRef][PubMed]
    [Google Scholar]
  9. Davis L. E., DeBiasi R., Goade D. E., Haaland K. Y., Harrington J. A., Harnar J. B., Pergam S. A., King M. K., DeMasters B. K., Tyler K. L.. 2006; West Nile virus neuroinvasive disease. Ann Neurol60:286–300 [CrossRef][PubMed]
    [Google Scholar]
  10. Glass W. G., Lim J. K., Cholera R., Pletnev A. G., Gao J. L., Murphy P. M.. 2005; Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection. J Exp Med202:1087–1098 [CrossRef][PubMed]
    [Google Scholar]
  11. Gralinski L. E., Ashley S. L., Dixon S. D., Spindler K. R.. 2009; Mouse adenovirus type 1-induced breakdown of the blood-brain barrier. J Virol83:9398–9410 [CrossRef][PubMed]
    [Google Scholar]
  12. Gubler D. J.. 2007; The continuing spread of West Nile virus in the western hemisphere. Clin Infect Dis45:1039–1046 [CrossRef][PubMed]
    [Google Scholar]
  13. Hayes E. B., Gubler D. J.. 2006; West Nile virus: epidemiology and clinical features of an emerging epidemic in the United States. Annu Rev Med57:181–194 [CrossRef][PubMed]
    [Google Scholar]
  14. Huber J. D., Egleton R. D., Davis T. P.. 2001; Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends Neurosci24:719–725 [CrossRef][PubMed]
    [Google Scholar]
  15. Kanlaya R., Pattanakitsakul S. N., Sinchaikul S., Chen S. T., Thongboonkerd V.. 2009; Alterations in actin cytoskeletal assembly and junctional protein complexes in human endothelial cells induced by dengue virus infection and mimicry of leukocyte transendothelial migration. J Proteome Res8:2551–2562 [CrossRef][PubMed]
    [Google Scholar]
  16. Kanmogne G. D., Schall K., Leibhart J., Knipe B., Gendelman H. E., Persidsky Y.. 2007; HIV-1 gp120 compromises blood-brain barrier integrity and enhances monocyte migration across blood-brain barrier: implication for viral neuropathogenesis. J Cereb Blood Flow Metab27:123–134 [CrossRef][PubMed]
    [Google Scholar]
  17. Kim Y. S., Kim S. S., Cho J. J., Choi D. H., Hwang O., Shin D. H., Chun H. S., Beal M. F., Joh T. H.. 2005; Matrix metalloproteinase-3: a novel signaling proteinase from apoptotic neuronal cells that activates microglia. J Neurosci25:3701–3711 [CrossRef][PubMed]
    [Google Scholar]
  18. King N. J., Getts D. R., Getts M. T., Rana S., Shrestha B., Kesson A. M.. 2007; Immunopathology of flavivirus infections. Immunol Cell Biol85:33–42 [CrossRef][PubMed]
    [Google Scholar]
  19. Klein R. S., Diamond M. S.. 2008; Immunological headgear: antiviral immune responses protect against neuroinvasive West Nile virus. Trends Mol Med14:286–294 [CrossRef][PubMed]
    [Google Scholar]
  20. 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 Virol79:11457–11466 [CrossRef][PubMed]
    [Google Scholar]
  21. Lanciotti R. S., Kerst A. J., Nasci R. S., Godsey M. S., Mitchell C. J., Savage H. M., Komar N., Panella N. A., Allen B. C.. other authors 2000; Rapid detection of West Nile virus from human clinical specimens, field-collected mosquitoes, and avian samples by a TaqMan reverse transcriptase-PCR assay. J Clin Microbiol38:4066–4071[PubMed]
    [Google Scholar]
  22. Lim J. K., Obara C. J., Rivollier A., Pletnev A. G., Kelsall B. L., Murphy P. M.. 2011; Chemokine receptor Ccr2 is critical for monocyte accumulation and survival in West Nile virus encephalitis. J Immunol186:471–478 [CrossRef][PubMed]
    [Google Scholar]
  23. Liu K. J., Rosenberg G. A.. 2005; Matrix metalloproteinases and free radicals in cerebral ischemia. Free Radic Biol Med39:71–80 [CrossRef][PubMed]
    [Google Scholar]
  24. Luabeya M. K., Dallasta L. M., Achim C. L., Pauza C. D., Hamilton R. L.. 2000; Blood-brain barrier disruption in simian immunodeficiency virus encephalitis. Neuropathol Appl Neurobiol26:454–462 [CrossRef][PubMed]
    [Google Scholar]
  25. Lustig S., Danenberg H. D., Kafri Y., Kobiler D., Ben-Nathan D.. 1992; Viral neuroinvasion and encephalitis induced by lipopolysaccharide and its mediators. J Exp Med176:707–712 [CrossRef][PubMed]
    [Google Scholar]
  26. Mishra M. K., Dutta K., Saheb S. K., Basu A.. 2009; Understanding the molecular mechanism of blood-brain barrier damage in an experimental model of Japanese encephalitis: correlation with minocycline administration as a therapeutic agent. Neurochem Int55:717–723 [CrossRef][PubMed]
    [Google Scholar]
  27. Morrey J. D., Olsen A. L., Siddharthan V., Motter N. E., Wang H., Taro B. S., Chen D., Ruffner D., Hall J. O.. 2008; Increased blood-brain barrier permeability is not a primary determinant for lethality of West Nile virus infection in rodents. J Gen Virol89:467–473 [CrossRef][PubMed]
    [Google Scholar]
  28. Mun-Bryce S., Lukes A., Wallace J., Lukes-Marx M., Rosenberg G. A.. 2002; Stromelysin-1 and gelatinase A are upregulated before TNF-α in LPS-stimulated neuroinflammation. Brain Res933:42–49 [CrossRef][PubMed]
    [Google Scholar]
  29. Persidsky Y., Ramirez S. H., Haorah J., Kanmogne G. D.. 2006; Blood-brain barrier: structural components and function under physiologic and pathologic conditions. J Neuroimmune Pharmacol1:223–236 [CrossRef][PubMed]
    [Google Scholar]
  30. Rosenberg G. A.. 1995; Matrix metalloproteinases in brain injury. J Neurotrauma12:833–842 [CrossRef][PubMed]
    [Google Scholar]
  31. Rosenberg G. A.. 2002; Matrix metalloproteinases in neuroinflammation. Glia39:279–291 [CrossRef][PubMed]
    [Google Scholar]
  32. Samuel M. A., Diamond M. S.. 2006; Pathogenesis of West Nile virus infection: a balance between virulence, innate and adaptive immunity, and viral evasion. J Virol80:9349–9360 [CrossRef][PubMed]
    [Google Scholar]
  33. Samuel M. A., Wang H., Siddharthan V., Morrey J. D., Diamond M. S.. 2007; Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis. Proc Natl Acad Sci U S A104:17140–17145 [CrossRef][PubMed]
    [Google Scholar]
  34. Schäfer A., Brooke C. B., Whitmore A. C., Johnston R. E.. 2011; The role of the blood-brain barrier during Venezuelan equine encephalitis virus infection. J Virol85:10682–10690 [CrossRef][PubMed]
    [Google Scholar]
  35. Suzuki Y., Nagai N., Umemura K., Collen D., Lijnen H. R.. 2007; Stromelysin-1 (MMP-3) is critical for intracranial bleeding after t-PA treatment of stroke in mice. J Thromb Haemost5:1732–1739 [CrossRef][PubMed]
    [Google Scholar]
  36. Tung W. H., Tsai H. W., Lee I. T., Hsieh H. L., Chen W. J., Chen Y. L., Yang C. M.. 2010; Japanese encephalitis virus induces matrix metalloproteinase-9 in rat brain astrocytes via NF-κB signalling dependent on MAPKs and reactive oxygen species. Br J Pharmacol161:1566–1583 [CrossRef][PubMed]
    [Google Scholar]
  37. Verma S., Lo Y., Chapagain M., Lum S., Kumar M., Gurjav U., Luo H., Nakatsuka A., Nerurkar V. R.. 2009; West Nile virus infection modulates human brain microvascular endothelial cells tight junction proteins and cell adhesion molecules: transmigration across the in vitro blood-brain barrier. Virology385:425–433 [CrossRef][PubMed]
    [Google Scholar]
  38. Verma S., Kumar M., Gurjav U., Lum S., Nerurkar V. R.. 2010; Reversal of West Nile virus-induced blood-brain barrier disruption and tight junction proteins degradation by matrix metalloproteinases inhibitor. Virology397:130–138 [CrossRef][PubMed]
    [Google Scholar]
  39. Verma S., Hoffmann F. W., Kumar M., Huang Z., Roe K., Nguyen-Wu E., Hashimoto A. S., Hoffmann P. R.. 2011; Selenoprotein K knockout mice exhibit deficient calcium flux in immune cells and impaired immune responses. J Immunol186:2127–2137 [CrossRef][PubMed]
    [Google Scholar]
  40. Wang T., Town T., Alexopoulou L., Anderson J. F., Fikrig E., Flavell R. A.. 2004; Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med10:1366–1373 [CrossRef][PubMed]
    [Google Scholar]
  41. Wang P., Dai J., Bai F., Kong K. F., Wong S. J., Montgomery R. R., Madri J. A., Fikrig E.. 2008a; Matrix metalloproteinase 9 facilitates West Nile virus entry into the brain. J Virol82:8978–8985 [CrossRef][PubMed]
    [Google Scholar]
  42. Wang S., Welte T., McGargill M., Town T., Thompson J., Anderson J. F., Flavell R. A., Fikrig E., Hedrick S. M., Wang T.. 2008b; Drak2 contributes to West Nile virus entry into the brain and lethal encephalitis. J Immunol181:2084–2091[PubMed][CrossRef]
    [Google Scholar]
  43. Zlokovic B. V.. 2008; The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron57:178–201 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.040899-0
Loading
/content/journal/jgv/10.1099/vir.0.040899-0
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

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