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Abstract

The molecular basis for the increased resistance of astrocytes to a non-neuropathogenic strain of West Nile virus (WNV), WNV-MAD78, compared with the neuropathogenic strain WNV-NY remains unclear. Here, we demonstrated that the reduced susceptibility of astrocytes to WNV-MAD78 is due to a combination of both cellular activities as well as viral determinants. Analyses of the viral particle indicated that astrocyte-derived WNV-MAD78 particles were less infectious than those of WNV-NY. Additionally, inhibition of cellular furin-like proteases increased WNV-MAD78 infectious particle production in astrocytes, suggesting that high levels of furin-like protease activity within these cells acted in a cell- and strain-specific manner to inhibit WNV-MAD78 replication. Moreover, analysis of recombinant viruses indicated that the structural proteins of WNV-MAD78 were responsible for decreased particle infectivity and the corresponding reduction in infectious particle production compared with WNV-NY. Thus, the composition of the WNV virion was also a major determinant for viral fitness within astrocytes and may contribute to WNV propagation within the central nervous system. Whether the WNV-MAD78 structural genes reduce virus replication and particle infectivity through the same mechanism as the cellular furin-like protease activity or whether these two determinants function through distinct pathways remains to be determined.

  • This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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2014-09-01
2022-10-06
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References

  1. Abbott N. J. 2002; Astrocyte–endothelial interactions and blood–brain barrier permeability. J Anat 200:629–638 [View Article][PubMed]
    [Google Scholar]
  2. Beasley D. W., Davis C. T., Whiteman M., Granwehr B., Kinney R. M., Barrett A. D. 2004; Molecular determinants of virulence of West Nile virus in North America. Arch Virol Suppl1835–41[PubMed]
    [Google Scholar]
  3. Beasley D. W., Whiteman M. C., Zhang S., Huang C. Y., Schneider B. S., Smith D. R., Gromowski G. D., Higgs S., Kinney R. M., Barrett A. D. 2005; Envelope protein glycosylation status influences mouse neuroinvasion phenotype of genetic lineage 1 West Nile virus strains. J Virol 79:8339–8347 [View Article][PubMed]
    [Google Scholar]
  4. Becker G. L., Lu Y., Hardes K., Strehlow B., Levesque C., Lindberg I., Sandvig K., Bakowsky U., Day R.other authors 2012; Highly potent inhibitors of proprotein convertase furin as potential drugs for treatment of infectious diseases. J Biol Chem 287:21992–22003 [View Article][PubMed]
    [Google Scholar]
  5. Botha E. M., Markotter W., Wolfaardt M., Paweska J. T., Swanepoel R., Palacios G., Nel L. H., Venter M. 2008; Genetic determinants of virulence in pathogenic lineage 2 West Nile virus strains. Emerg Infect Dis 14:222–230 [View Article][PubMed]
    [Google Scholar]
  6. Brinton M. A. 2002; The molecular biology of West Nile Virus: a new invader of the western hemisphere. Annu Rev Microbiol 56:371–402 [View Article][PubMed]
    [Google Scholar]
  7. Cho H., Diamond M. S. 2012; Immune responses to West Nile virus infection in the central nervous system. Viruses 4:3812–3830 [View Article][PubMed]
    [Google Scholar]
  8. Colpitts T. M., Rodenhuis-Zybert I., Moesker B., Wang P., Fikrig E., Smit J. M. 2011; prM-antibody renders immature West Nile virus infectious in vivo. J Gen Virol 92:2281–2285 [View Article][PubMed]
    [Google Scholar]
  9. Davis C. W., Mattei L. M., Nguyen H. Y., Ansarah-Sobrinho C., Doms R. W., Pierson T. C. 2006a; The location of asparagine-linked glycans on West Nile virions controls their interactions with CD209 (dendritic cell-specific ICAM-3 grabbing nonintegrin). J Biol Chem 281:37183–37194 [View Article][PubMed]
    [Google Scholar]
  10. Davis C. W., Nguyen H. Y., Hanna S. L., Sánchez M. D., Doms R. W., Pierson T. C. 2006b; West Nile virus discriminates between DC-SIGN and DC-SIGNR for cellular attachment and infection. J Virol 80:1290–1301 [View Article][PubMed]
    [Google Scholar]
  11. Deiva K., Khiati A., Hery C., Salim H., Leclerc P., Horellou P., Tardieu M. 2006; CCR5-, DC-SIGN-dependent endocytosis and delayed reverse transcription after human immunodeficiency virus type 1 infection in human astrocytes. AIDS Res Hum Retroviruses 22:1152–1161 [View Article][PubMed]
    [Google Scholar]
  12. Diamond M. S., Pierson T. C., Fremont D. H. 2008; The structural immunology of antibody protection against West Nile virus. Immunol Rev 225:212–225 [View Article][PubMed]
    [Google Scholar]
  13. Gómez R. M., Yep A., Schattner M., Berría M. I. 2003; Junin virus-induced astrocytosis is impaired by iNOS inhibition. J Med Virol 69:145–149 [View Article][PubMed]
    [Google Scholar]
  14. Hanna S. L., Pierson T. C., Sanchez M. D., Ahmed A. A., Murtadha M. M., Doms R. W. 2005; N-linked glycosylation of West Nile virus envelope proteins influences particle assembly and infectivity. J Virol 79:13262–13274 [View Article][PubMed]
    [Google Scholar]
  15. Hobson-Peters J., Toye P., Sánchez M. D., Bossart K. N., Wang L. F., Clark D. C., Cheah W. Y., Hall R. A. 2008; A glycosylated peptide in the West Nile virus envelope protein is immunogenic during equine infection. J Gen Virol 89:3063–3072 [View Article][PubMed]
    [Google Scholar]
  16. Hu G., Yao H., Chaudhuri A. D., Duan M., Yelamanchili S. V., Wen H., Cheney P. D., Fox H. S., Buch S. 2012; Exosome-mediated shuttling of microRNA-29 regulates HIV Tat and morphine-mediated neuronal dysfunction. Cell Death Dis 3:e381 [View Article][PubMed]
    [Google Scholar]
  17. 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]
  18. 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]
  19. 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]
  20. Li J., Hu S., Zhou L., Ye L., Wang X., Ho J., Ho W. 2011; Interferon lambda inhibits herpes simplex virus type I infection of human astrocytes and neurons. Glia 59:58–67 [View Article][PubMed]
    [Google Scholar]
  21. Martina B. E., Koraka P., van den Doel P., Rimmelzwaan G. F., Haagmans B. L., Osterhaus A. D. 2008; DC-SIGN enhances infection of cells with glycosylated West Nile virus in vitro and virus replication in human dendritic cells induces production of IFN-alpha and TNF-alpha. Virus Res 135:64–71 [View Article][PubMed]
    [Google Scholar]
  22. Mukherjee S., Lin T. Y., Dowd K. A., Manhart C. J., Pierson T. C. 2011; The infectivity of prM-containing partially mature West Nile virus does not require the activity of cellular furin-like proteases. J Virol 85:12067–12072 [View Article][PubMed]
    [Google Scholar]
  23. Nelson S., Jost C. A., Xu Q., Ess J., Martin J. E., Oliphant T., Whitehead S. S., Durbin A. P., Graham B. S.other authors 2008; Maturation of West Nile virus modulates sensitivity to antibody-mediated neutralization. PLoS Pathog 4:e1000060 [View Article][PubMed]
    [Google Scholar]
  24. Pierson T. C., Diamond M. S. 2012; Degrees of maturity: the complex structure and biology of flaviviruses. Curr Opin Virol 2:168–175 [View Article][PubMed]
    [Google Scholar]
  25. Roe K., Kumar M., Lum S., Orillo B., Nerurkar V. R., Verma S. 2012; West Nile virus-induced disruption of the blood–brain barrier in mice is characterized by the degradation of the junctional complex proteins and increase in multiple matrix metalloproteinases. J Gen Virol 93:1193–1203 [View Article][PubMed]
    [Google Scholar]
  26. Scherret J. H., Mackenzie J. S., Khromykh A. A., Hall R. A. 2001; Biological significance of glycosylation of the envelope protein of Kunjin virus. Ann N Y Acad Sci 951:361–363 [View Article][PubMed]
    [Google Scholar]
  27. Shi P. Y., Tilgner M., Lo M. K., Kent K. A., Bernard K. A. 2002; Infectious cDNA clone of the epidemic West Nile virus from New York City. J Virol 76:5847–5856 [View Article][PubMed]
    [Google Scholar]
  28. Stadler K., Allison S. L., Schalich J., Heinz F. X. 1997; Proteolytic activation of tick-borne encephalitis virus by furin. J Virol 71:8475–8481[PubMed]
    [Google Scholar]
  29. Stins M. F., Shen Y., Huang S. H., Gilles F., Kalra V. K., Kim K. S. 2001; Gp120 activates children’s brain endothelial cells via CD4. J Neurovirol 7:125–134 [View Article][PubMed]
    [Google Scholar]
  30. Suthar M. S., Brassil M. M., Blahnik G., Gale M. Jr 2012; Infectious clones of novel lineage 1 and lineage 2 West Nile virus strains WNV-TX02 and WNV-Madagascar. J Virol 86:7704–7709 [View Article][PubMed]
    [Google Scholar]
  31. van Marle G., Antony J., Ostermann H., Dunham C., Hunt T., Halliday W., Maingat F., Urbanowski M. D., Hobman T.other authors 2007; West Nile virus-induced neuroinflammation: glial infection and capsid protein-mediated neurovirulence. J Virol 81:10933–10949 [View Article][PubMed]
    [Google Scholar]
  32. Vandergaast R., Hoover L. I., Zheng K., Fredericksen B. L. 2014; Generation of West Nile virus infectious clones containing amino acid insertions between capsid and capsid anchor. Viruses 6:1637–1653 [View Article][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 [View Article][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 [View Article][PubMed]
    [Google Scholar]
  35. Wang Z., Trillo-Pazos G., Kim S. Y., Canki M., Morgello S., Sharer L. R., Gelbard H. A., Su Z. Z., Kang D. C.other authors 2004; Effects of human immunodeficiency virus type 1 on astrocyte gene expression and function: potential role in neuropathogenesis. J Neurovirol 10:Suppl 125–32 [View Article][PubMed]
    [Google Scholar]
  36. Zybert I. A., van der Ende-Metselaar H., Wilschut J., Smit J. M. 2008; Functional importance of dengue virus maturation: infectious properties of immature virions. J Gen Virol 89:3047–3051 [View Article][PubMed]
    [Google Scholar]
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