1887

Abstract

Human cerebral microvascular endothelial cells (hCMEC/D3 cell line) form a steady polarized barrier when cultured on a permeable membrane. Their susceptibility to enterovirus (EV) strains was analysed to investigate how these viruses may cross the blood–brain barrier. A sample of 88 virus strains was selected on phylogenetic features amongst 43 epidemiologically relevant types of the four EV species A–D. The EV-A71 genome was replicated at substantial rates, whilst the infectious virus was released at extremely low but sustained rates at both barrier sides for at least 4 days. EV-A71 antigens were detected in a limited number of cells. The properties of the endothelial barrier (structure and permeability) remained intact throughout infection. The chronic EV-A71 infection was in sharp contrast to the productive infection of cytolytic EVs (e.g. echoviruses E-6 and E-30). The hCMEC/D3 barriers infected with the latter EVs exhibited elevated proportions of apoptotic and necrotic cells, which resulted in major injuries to the endothelial barriers with a dramatic increase of paracellular permeability and virus crossing to the abluminal side. The following intracellular rearrangements were also seen: early destruction of the actin cytoskeleton, remodelling of intracellular membranes and reorganization of the mitochondrion network in a small cluster near the perinuclear space.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.000103
2015-07-01
2019-12-13
Loading full text...

Full text loading...

/deliver/fulltext/jgv/96/7/1682.html?itemId=/content/journal/jgv/10.1099/vir.0.000103&mimeType=html&fmt=ahah

References

  1. Agol V. I., Gmyl A. P.. ( 2010; ). Viral security proteins: counteracting host defences. . Nat Rev Microbiol 8:, 867–878. [CrossRef] [PubMed]
    [Google Scholar]
  2. Antona D., Lévêque N., Chomel J. J., Dubrou S., Lévy-Bruhl D., Lina B.. ( 2007; ). Surveillance of enteroviruses in France, 2000–2004. . Eur J Clin Microbiol Infect Dis 26:, 403–412. [CrossRef] [PubMed]
    [Google Scholar]
  3. Bailly J. L., Chambon M., Peigue-Lafeuille H., Laveran H., De Champs C., Beytout D.. ( 1991; ). Activity of glutaraldehyde at low concentrations (less than 2%) against poliovirus and its relevance to gastrointestinal endoscope disinfection procedures. . Appl Environ Microbiol 57:, 1156–1160.[PubMed]
    [Google Scholar]
  4. Belov G. A., Nair V., Hansen B. T., Hoyt F. H., Fischer E. R., Ehrenfeld E.. ( 2012; ). Complex dynamic development of poliovirus membranous replication complexes. . J Virol 86:, 302–312. [CrossRef] [PubMed]
    [Google Scholar]
  5. Bergelson J. M., St John N., Kawaguchi S., Chan M., Stubdal H., Modlin J., Finberg R. W.. ( 1993; ). Infection by echoviruses 1 and 8 depends on the alpha 2 subunit of human VLA-2. . J Virol 67:, 6847–6852.[PubMed]
    [Google Scholar]
  6. Bergelson J. M., Chan M., Solomon K. R., St John N. F., Lin H., Finberg R. W.. ( 1994; ). Decay-accelerating factor (CD55), a glycosylphosphatidylinositol-anchored complement regulatory protein, is a receptor for several echoviruses. . Proc Natl Acad Sci U S A 91:, 6245–6248. [CrossRef] [PubMed]
    [Google Scholar]
  7. Bozym R. A., Morosky S. A., Kim K. S., Cherry S., Coyne C. B.. ( 2010; ). Release of intracellular calcium stores facilitates coxsackievirus entry into polarized endothelial cells. . PLoS Pathog 6:, e1001135. [CrossRef] [PubMed]
    [Google Scholar]
  8. Chen C. S., Yao Y. C., Lin S. C., Lee Y. P., Wang Y. F., Wang J. R., Liu C. C., Lei H. Y., Yu C. K.. ( 2007; ). Retrograde axonal transport: a major transmission route of enterovirus 71 in mice. . J Virol 81:, 8996–9003. [CrossRef] [PubMed]
    [Google Scholar]
  9. Cheng H. Y., Huang Y. C., Yen T. Y., Hsia S. H., Hsieh Y. C., Li C. C., Chang L. Y., Huang L. M.. ( 2014; ). The correlation between the presence of viremia and clinical severity in patients with enterovirus 71 infection: a multi-center cohort study. . BMC Infect Dis 14:, 417. [CrossRef] [PubMed]
    [Google Scholar]
  10. Conaldi P. G., Serra C., Mossa A., Falcone V., Basolo F., Camussi G., Dolei A., Toniolo A.. ( 1997; ). Persistent infection of human vascular endothelial cells by group B coxsackieviruses. . J Infect Dis 175:, 693–696. [CrossRef] [PubMed]
    [Google Scholar]
  11. Coyne C. B., Kim K. S., Bergelson J. M.. ( 2007; ). Poliovirus entry into human brain microvascular cells requires receptor-induced activation of SHP-2. . EMBO J 26:, 4016–4028. [CrossRef] [PubMed]
    [Google Scholar]
  12. Eberle K. E., Nguyen V. T., Freistadt M. S.. ( 1995; ). Low levels of poliovirus replication in primary human monocytes: possible interactions with lymphocytes. . Arch Virol 140:, 2135–2150. [CrossRef] [PubMed]
    [Google Scholar]
  13. Engelhardt B., Coisne C.. ( 2011; ). Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle. . Fluids Barriers CNS 8:, 4. [CrossRef] [PubMed]
    [Google Scholar]
  14. Gromeier M., Wimmer E.. ( 1998; ). Mechanism of injury-provoked poliomyelitis. . J Virol 72:, 5056–5060.[PubMed]
    [Google Scholar]
  15. Haddad A., Nokhbeh M. R., Alexander D. A., Dawe S. J., Grisé C., Gulzar N., Dimock K.. ( 2004; ). Binding to decay-accelerating factor is not required for infection of human leukocyte cell lines by enterovirus 70. . J Virol 78:, 2674–2681. [CrossRef] [PubMed]
    [Google Scholar]
  16. Khetsuriani N., Lamonte-Fowlkes A., Oberst S., Pallansch M. A..Centers for Disease Control and Prevention ( 2006; ). Enterovirus surveillance – United States, 1970–2005. . MMWR Surveill Summ 55:, 1–20.[PubMed]
    [Google Scholar]
  17. Khong W. X., Yan B., Yeo H., Tan E. L., Lee J. J., Ng J. K., Chow V. T., Alonso S.. ( 2012; ). A non-mouse-adapted enterovirus 71 (EV71) strain exhibits neurotropism, causing neurological manifestations in a novel mouse model of EV71 infection. . J Virol 86:, 2121–2131. [CrossRef] [PubMed]
    [Google Scholar]
  18. Kim S., Kim H. Y., Lee S., Kim S. W., Sohn S., Kim K., Cho H.. ( 2007; ). Hepatitis B virus X protein induces perinuclear mitochondrial clustering in microtubule- and Dynein-dependent manners. . J Virol 81:, 1714–1726. [CrossRef] [PubMed]
    [Google Scholar]
  19. Lancaster K. Z., Pfeiffer J. K.. ( 2010; ). Limited trafficking of a neurotropic virus through inefficient retrograde axonal transport and the type I interferon response. . PLoS Pathog 6:, e1000791. [CrossRef] [PubMed]
    [Google Scholar]
  20. Liang C. C., Sun M. J., Lei H. Y., Chen S. H., Yu C. K., Liu C. C., Wang J. R., Yeh T. M.. ( 2004; ). Human endothelial cell activation and apoptosis induced by enterovirus 71 infection. . J Med Virol 74:, 597–603. [CrossRef] [PubMed]
    [Google Scholar]
  21. Limpens R. W., van der Schaar H. M., Kumar D., Koster A. J., Snijder E. J., van Kuppeveld F. J., Bárcena M.. ( 2011; ). The transformation of enterovirus replication structures: a three-dimensional study of single- and double-membrane compartments. . MBio 2:, 00166-11. [CrossRef] [PubMed]
    [Google Scholar]
  22. Merilahti P., Koskinen S., Heikkilä O., Karelehto E., Susi P.. ( 2012; ). Endocytosis of integrin-binding human picornaviruses. . Adv Virol 2012:, 547530. [CrossRef] [PubMed]
    [Google Scholar]
  23. Nishikawa M., Matsubara T., Yoshitomi T., Ichiyama T., Hayashi T., Furukawa S.. ( 2000; ). Abnormalities of brain perfusion in echovirus type 30 meningitis. . J Neurol Sci 179:, 122–126. [CrossRef] [PubMed]
    [Google Scholar]
  24. Ohka S., Nihei C., Yamazaki M., Nomoto A.. ( 2012; ). Poliovirus trafficking toward central nervous system via human poliovirus receptor-dependent and -independent pathway. . Front Microbiol 3:, 147. [CrossRef] [PubMed]
    [Google Scholar]
  25. Ren R., Racaniello V. R.. ( 1992; ). Poliovirus spreads from muscle to the central nervous system by neural pathways. . J Infect Dis 166:, 747–752. [CrossRef] [PubMed]
    [Google Scholar]
  26. Rojo G., Chamorro M., Salas M. L., Viñuela E., Cuezva J. M., Salas J.. ( 1998; ). Migration of mitochondria to viral assembly sites in African swine fever virus-infected cells. . J Virol 72:, 7583–7588.[PubMed]
    [Google Scholar]
  27. Rotbart H. A.. ( 1995; ). Meningitis and encephalitis. . In Human Enterovirus Infections, pp. 271–289. Edited by Rotbart H. A... Washington, DC:: American Society for Microbiology;. [CrossRef]
    [Google Scholar]
  28. Sabin A. B.. ( 1956; ). Pathogenesis of poliomyelitis; reappraisal in the light of new data. . Science 123:, 1151–1157. [CrossRef] [PubMed]
    [Google Scholar]
  29. Saijets S., Ylipaasto P., Vaarala O., Hovi T., Roivainen M.. ( 2003; ). Enterovirus infection and activation of human umbilical vein endothelial cells. . J Med Virol 70:, 430–439. [CrossRef] [PubMed]
    [Google Scholar]
  30. Spindler K. R., Hsu T. H.. ( 2012; ). Viral disruption of the blood–brain barrier. . Trends Microbiol 20:, 282–290. [CrossRef] [PubMed]
    [Google Scholar]
  31. Stamatovic S. M., Sladojevic N., Keep R. F., Andjelkovic A. V.. ( 2012; ). Relocalization of junctional adhesion molecule A during inflammatory stimulation of brain endothelial cells. . Mol Cell Biol 32:, 3414–3427. [CrossRef] [PubMed]
    [Google Scholar]
  32. Tabor-Godwin J. M., Ruller C. M., Bagalso N., An N., Pagarigan R. R., Harkins S., Gilbert P. E., Kiosses W. B., Gude N. A. et al. ( 2010; ). A novel population of myeloid cells responding to coxsackievirus infection assists in the dissemination of virus within the neonatal CNS. . J Neurosci 30:, 8676–8691. [CrossRef] [PubMed]
    [Google Scholar]
  33. 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. . Virology 385:, 425–433. [CrossRef] [PubMed]
    [Google Scholar]
  34. 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. . Virology 397:, 130–138. [CrossRef] [PubMed]
    [Google Scholar]
  35. Volle R., Nourrisson C., Mirand A., Regagnon C., Chambon M., Henquell C., Bailly J. L., Peigue-Lafeuille H., Archimbaud C.. ( 2012; ). Quantitative real-time RT-PCR assay for research studies on enterovirus infections in the central nervous system. . J Virol Methods 185:, 142–148. [CrossRef] [PubMed]
    [Google Scholar]
  36. Volle R., Bailly J. L., Mirand A., Pereira B., Marque-Juillet S., Chambon M., Regagnon C., Brebion A., Henquell C. et al. ( 2014; ). Variations in cerebrospinal fluid viral loads among enterovirus genotypes in patients hospitalized with laboratory-confirmed meningitis due to enterovirus. . J Infect Dis 210:, 576–584. [CrossRef] [PubMed]
    [Google Scholar]
  37. Vuorinen T., Vainionpää R., Vanharanta R., Hyypiä T.. ( 1996; ). Susceptibility of human bone marrow cells and hematopoietic cell lines to coxsackievirus B3 infection. . J Virol 70:, 9018–9023.[PubMed]
    [Google Scholar]
  38. Wahid R., Cannon M. J., Chow M.. ( 2005; a). Virus-specific CD4+ and CD8+ cytotoxic T-cell responses and long-term T-cell memory in individuals vaccinated against polio. . J Virol 79:, 5988–5995. [CrossRef] [PubMed]
    [Google Scholar]
  39. Wahid R., Cannon M. J., Chow M.. ( 2005; b). Dendritic cells and macrophages are productively infected by poliovirus. . J Virol 79:, 401–409. [CrossRef] [PubMed]
    [Google Scholar]
  40. Weksler B. B., Subileau E. A., Perrière N., Charneau P., Holloway K., Leveque M., Tricoire-Leignel H., Nicotra A., Bourdoulous S. et al. ( 2005; ). Blood–brain barrier-specific properties of a human adult brain endothelial cell line. . FASEB J 19:, 1872–1874.[PubMed]
    [Google Scholar]
  41. Weksler B., Romero I. A., Couraud P. O.. ( 2013; ). The hCMEC/D3 cell line as a model of the human blood brain barrier. . Fluids Barriers CNS 10:, 16. [CrossRef] [PubMed]
    [Google Scholar]
  42. Yang W. X., Terasaki T., Shiroki K., Ohka S., Aoki J., Tanabe S., Nomura T., Terada E., Sugiyama Y., Nomoto A.. ( 1997; ). Efficient delivery of circulating poliovirus to the central nervous system independently of poliovirus receptor. . Virology 229:, 421–428. [CrossRef] [PubMed]
    [Google Scholar]
  43. Yen M. H., Tsao K. C., Huang Y. C., Huang C. G., Huang Y. L., Lin R., Chang M. L., Huang C. C., Yan D. C., Lin T. Y.. ( 2007; ). Viral load in blood is correlated with disease severity of neonatal coxsackievirus B3 infection: early diagnosis and predicting disease severity is possible in severe neonatal enterovirus infection. . Clin Infect Dis 44:, e78–e81. [CrossRef] [PubMed]
    [Google Scholar]
  44. Ylipaasto P., Eskelinen M., Salmela K., Hovi T., Roivainen M.. ( 2010; ). Vitronectin receptors, αv integrins, are recognized by several non-RGD-containing echoviruses in a continuous laboratory cell line and also in primary human Langerhans’ islets and endothelial cells. . J Gen Virol 91:, 155–165. [CrossRef] [PubMed]
    [Google Scholar]
  45. Zanone M. M., Favaro E., Conaldi P. G., Greening J., Bottelli A., Perin P. C., Klein N. J., Peakman M., Camussi G.. ( 2003; ). Persistent infection of human microvascular endothelial cells by coxsackie B viruses induces increased expression of adhesion molecules. . J Immunol 171:, 438–446. [CrossRef] [PubMed]
    [Google Scholar]
  46. Zhang Y., Cui W., Liu L., Wang J., Zhao H., Liao Y., Na R., Dong C., Wang L. et al. ( 2011; ). Pathogenesis study of enterovirus 71 infection in rhesus monkeys. . Lab Invest 91:, 1337–1350. [CrossRef] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.000103
Loading
/content/journal/jgv/10.1099/vir.0.000103
Loading

Data & Media loading...

Supplements

Supplementary Data



PDF

Most Cited This Month

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