1887

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Volume 87, Issue 6

Bovine respiratory syncytial virus lacking the virokinin or with a mutation in furin cleavage site RA(R/K)R induces less pulmonary inflammation without impeding the induction of protective immunity in calves Free

Abstract

The BRSV fusion (F) protein is cleaved at two furin consensus sequence sites, resulting in the generation of disulphide-linked F1 and F2 subunits and the release of an intervening peptide of 27 amino acids (pep27), which is converted into a biologically active tachykinin (virokinin). The role of the virokinin and the importance of one of the furin cleavage sites, FCS-2 [RA(R/K)R], in the pathogenesis of BRSV infection and in the subsequent development of immunity was studied in gnotobiotic calves infected with a recombinant BRSV (rBRSV) lacking pep27 (rBRSVΔp27) or with rBRSV108/109, which contains two amino acid substitutions in FCS-2 (RANN). Although replication of the mutant viruses and the parental wild-type (WT) rBRSV in the lungs was similar, the extent of gross and microscopic lesions induced by the mutant viruses was less than that induced by WT rBRSV. Furthermore, the numbers of eosinophils in the lungs of calves infected with the mutant viruses were significantly less than that in calves infected with WT virus. These observations suggest a role for the virokinin in the pathogenesis of BRSV infection. Following mucosal immunization with rBRSVΔp27, the levels of BRSV-specific serum antibodies were similar to those induced by WT virus. In contrast, the level of neutralizing antibodies induced by rBRSV108/109 was 10-fold lower than that induced by WT virus. Nevertheless, resistance to BRSV challenge induced by the mutant and WT viruses was similar, suggesting that neither pep27 nor FCS-2 plays a major role in the induction of protective immunity.

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2006-06-01
2024-04-28
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References

  1. Antonis A. F., Schrijver R. S., Daus F., Steverink P. J., Stockhofe N., Hensen E. J., Langedijk J. P., van der Most R. G. 2003; Vaccine-induced immunopathology during bovine respiratory syncytial virus infection: exploring the parameters of pathogenesis. J Virol 77:12067–12073 [CrossRef]
     [Google Scholar]
  2. Begona Ruiz-Arguello M., Gonzalez-Reyes L., Calder L. J., Palomo C., Martin D., Saiz M. J., Garcia-Barreno B., Skehel J. J., Melero J. A. 2002; Effect of proteolytic processing at two distinct sites on shape and aggregation of an anchorless fusion protein of human respiratory syncytial virus and fate of the intervening segment. Virology 298:317–326 [CrossRef]
     [Google Scholar]
  3. Cao T., Pinter E., Al-Rashed S., Gerard N., Hoult J. R., Brain S. D. 2000; Neurokinin-1 receptor agonists are involved in mediating neutrophil accumulation in the inflamed, but not normal, cutaneous microvasculature: an in vivo study using neurokinin-1 receptor knockout mice. J Immunol 164:5424–5429 [CrossRef]
     [Google Scholar]
  4. Collins P. L., Murphy B. R. 2002; Respiratory syncytial virus: reverse genetics and vaccine strategies. Virology 296:204–211 [CrossRef]
     [Google Scholar]
  5. Dennis M. J., Davis D. C., Hoare M. N. 1976; A simplified apparatus for the microbiological isolation of calves. Br Vet J 132:642–646
     [Google Scholar]
  6. Di Maria G. U., Bellofiore S., Geppetti P. 1998; Regulation of airway neurogenic inflammation by neutral endopeptidase. Eur Respir J 12:1454–1462 [CrossRef]
     [Google Scholar]
  7. Domachowske J. B., Bonville C. A., Rosenberg E. S. 2001; Gene expression in epithelial cells in response to pneumovirus infection. Respir Res 2:225–233 [CrossRef]
     [Google Scholar]
  8. Gaddum R. M., Cook R. S., Furze J. M., Ellis S. A., Taylor G. 2003; Recognition of bovine respiratory syncytial virus proteins by bovine CD8+ T lymphocytes. Immunology 108:220–229 [CrossRef]
     [Google Scholar]
  9. Garofalo R., Kimpen J. L. L., Welliver R. C., Ogra P. L. 1992; Eosinophil degranulation in the respiratory tract during naturally acquired respiratory syncytial virus infection. J Pediatr 120:28–32 [CrossRef]
     [Google Scholar]
  10. Goetzl E. J., Sreedharan S. P. 1992; Mediators of communication and adaptation in the neuroendocrine and immune systems. FASEB J 6:2646–2652
     [Google Scholar]
  11. Gonzalez-Reyes L., Ruiz-Arguello M. B., Garcia-Barreno B., Calder L., Lopez J. A., Albar J. P., Skehel J. J., Wiley D. C., Melero J. A. 2001; Cleavage of the human respiratory syncytial virus fusion protein at two distinct sites is required for activation of membrane fusion. Proc Natl Acad Sci U S A 98:9859–9864 [CrossRef]
     [Google Scholar]
  12. Hall C. B., Douglas R. G. Jr, Geiman J. M. 1976; Respiratory syncytial virus infections in infants: quantitation and duration of shedding. J Pediatr 89:11–15 [CrossRef]
     [Google Scholar]
  13. Harrison A. M., Bonville C. A., Rosenberg H. F., Domachowske J. B. 1999; Respiratory syncytial virus-induced chemokine expression in the lower airways: eosinophil recruitment and degranulation. Am J Respir Crit Care Med 159:1918–1924 [CrossRef]
     [Google Scholar]
  14. Hirata A., Motojima S., Fukuda T., Makino S. 1996; Damage to respiratory epithelium by guinea-pig eosinophils stimulated with IgG-coated Sepharose beads. Clin Exp Allergy 26:848–858 [CrossRef]
     [Google Scholar]
  15. Hisamatsu K., Ganbo T., Nakazawa T., Murakami Y., Gleich G. J., Makiyama K., Koyama H. 1990; Cytotoxicity of human eosinophil granule major basic protein to human nasal sinus mucosa in vitro. J Allergy Clin Immunol 86:52–63 [CrossRef]
     [Google Scholar]
  16. Howard C. J., Morrison W. I., Mackay C. R., Splitter G. A. 1991; Leukocyte antigens in cattle, sheep and goats. Proceedings of the First International Workshop on Leukocyte Antigens in Cattle, Sheep and Goats. Vet Immunol Immunopathol 27:1–94 [CrossRef]
     [Google Scholar]
  17. Karger A., Schmidt U., Buchholz U. J. 2001; Recombinant bovine respiratory syncytial virus with deletions of the G or SH genes: G and F proteins bind heparin. J Gen Virol 82:631–640
     [Google Scholar]
  18. Kennedy H. E., Jones B. V., Tucker E. M., Ford N. J., Clarke S. W., Furze J. M., Thomas L. H., Stott E. J. 1988; Production and characterisation of bovine monoclonal antibodies to respiratory syncytial virus. J Gen Virol 69:3023–3032 [CrossRef]
     [Google Scholar]
  19. Liu C. M., Okuda M. 1988; Injurious effect of eosinophil extract on the human nasal mucosa. Rhinology 26:121–132
     [Google Scholar]
  20. Maggi C. A. 1997; The effects of tachykinins on inflammatory and immune cells. Regul Pept 70:75–90 [CrossRef]
     [Google Scholar]
  21. McGillis J. P., Mitsuhashi M., Payan D. G. 1990; Immunomodulation by tachykinin neuropeptides. Ann N Y Acad Sci 594:85–94 [CrossRef]
     [Google Scholar]
  22. McNamara P. S., Flanagan B. F., Hart C. A., Smyth R. L. 2005; Production of chemokines in the lungs of infants with severe respiratory syncytial virus bronchiolitis. J Infect Dis 191:1225–1232 [CrossRef]
     [Google Scholar]
  23. Mohanty S. B., Ingling A. L., Lillie M. G. 1975; Experimentally induced respiratory syncytial viral infection in calves. Am J Vet Res 36:417–419
     [Google Scholar]
  24. Noah T., Becker S. 2000; Chemokines in nasal secretions of normal adults experimentally infected with respiratory syncytial virus. Clin Immunol 97:43–49 [CrossRef]
     [Google Scholar]
  25. Numao T., Agrawal D. K. 1992; Neuropeptides modulate human eosinophil chemotaxis. J Immunol 149:3309–3315
     [Google Scholar]
  26. Olszewska-Pazdrak B., Casola A., Saito T., Alam R., Crowe S. E., Mei F., Ogra P. L., Garofola R. P. 1998; Cell-specific expression of RANTES, MCP-1 and MIP-1a by lower airway epithelial cells and eosinophils infected with respiratory syncytial virus. J Virol 72:4756–4764
     [Google Scholar]
  27. Patacchini R., Lecci A., Holzer P., Maggi C. A. 2004; Newly discovered tachykinins raise new questions about their peripheral roles and the tachykinin nomenclature. Trends Pharmacol Sci 25:1–3 [CrossRef]
     [Google Scholar]
  28. Pennefather J. N., Lecci A., Candenas M. L., Patak E., Pinto F. M., Maggi C. A. 2004; Tachykinins and tachykinin receptors: a growing family. Life Sci 74:1445–1463 [CrossRef]
     [Google Scholar]
  29. Prince G. A., Curtis S. J., Yim K. C., Porter D. D. 2001; Vaccine-enhanced respiratory syncytial virus disease in cotton rats following immunization with Lot 100 or a newly prepared reference vaccine. J Gen Virol 82:2881–2888
     [Google Scholar]
  30. Rosenberg H. F., Domachowske J. B. 2001; Eosinophils, eosinophil ribonucleases, and their role in host defense against respiratory virus pathogens. J Leukoc Biol 70:691–698
     [Google Scholar]
  31. Schmidt U., Breyer J., Polster U., Gershwin L. J., Buchholz U. 2002; Mucosal immunization with live recombinant bovine respiratory syncytial virus (BRSV) and recombinant BRSV lacking the envelope glycoprotein G protects against challenge with wild-type BRSV. J Virol 76:12355–12359 [CrossRef]
     [Google Scholar]
  32. Schreiber P., Matheise J. P., Dessy F., Heimann M., Letesson J. J., Coppe P., Collard A. 2000; High mortality rate associated with bovine respiratory syncytial virus (BRSV) infection in Belgian white blue calves previously vaccinated with an inactivated BRSV vaccine. J Vet Med B Infect Dis Vet Public Health 47:535–550 [CrossRef]
     [Google Scholar]
  33. Soukup J. M., Becker S. 2003; Role of monocytes and eosinophils in human respiratory syncytial virus infection in vitro. Clin Immunol 107:178–185 [CrossRef]
     [Google Scholar]
  34. Stott E. J., Taylor G. 1985; Respiratory syncytial virus. Brief review. Arch Virol 84:1–52
     [Google Scholar]
  35. Stott E. J., Thomas L. H., Taylor G., Collins A. P., Jebbett J., Crouch S. 1984; A comparison of three vaccines against respiratory syncytial virus in calves. J Hyg 93:251–261 [CrossRef]
     [Google Scholar]
  36. Tam E. K., Caughey G. H. 1990; Degradation of airway neuropeptides by human lung tryptase. Am J Respir Cell Mol Biol 3:27–32 [CrossRef]
     [Google Scholar]
  37. Taylor G., Stott E. J., Furze J., Ford J., Sopp P. 1992; Protective epitopes on the fusion protein of respiratory syncytial virus recognized by murine and bovine monoclonal antibodies. J Gen Virol 73:2217–2223 [CrossRef]
     [Google Scholar]
  38. Taylor G., Thomas L. H., Wyld S. G., Furze J., Sopp P., Howard C. J. 1995; Role of T-lymphocyte subsets in recovery from respiratory syncytial virus infection in calves. J Virol 69:6658–6664
     [Google Scholar]
  39. Taylor G., Thomas L. H., Furze J. M., Cook R. S., Wyld S. G., Lerch R., Hardy R., Wertz G. W. 1997; Recombinant vaccinia viruses expressing the F, G or N, but not the M2, protein of bovine respiratory syncytial virus (BRSV) induce resistance to BRSV challenge in the calf and protect against the development of pneumonic lesions. J Gen Virol 78:3195–3206
     [Google Scholar]
  40. Thomas L. H., Gourlay R. N., Stott E. J., Howard C. J., Bridger J. C. 1982; A search for new microorganisms in calf pneumonia by the inoculation of gnotobiotic calves. Res Vet Sci 33:170–182
     [Google Scholar]
  41. Thomas L. H., Stott E. J., Collins A. P., Jebbett J. 1984; Experimental pneumonia in gnotobiotic calves produced by respiratory syncytial virus. Br J Exp Pathol 65:19–28
     [Google Scholar]
  42. Tiberio I. F., Leick-Maldonado E. A., Miyahara L., Kasahara D. I., Spilborghs G. M., Martins M. A., Saldiva P. H. 2003; Effects of neurokinins on airway and alveolar eosinophil recruitment. Exp Lung Res 29:165–177 [CrossRef]
     [Google Scholar]
  43. Valarcher J. F., Bourhy H., Gelfi J., Schelcher F. 1999; Evaluation of a nested reverse transcription-PCR assay based on the nucleoprotein gene for diagnosis of spontaneous and experimental bovine respiratory syncytial virus infections. J Clin Microbiol 37:1858–1862
     [Google Scholar]
  44. Valarcher J.-F., Furze J., Wyld S., Cook R., Conzelmann K.-K., Taylor G. 2003; Role of type I interferons in the attenuation and immunogenicity of recombinant bovine respiratory syncytial viruses (BRSV) lacking NS proteins. J Virol 77:8426–8439 [CrossRef]
     [Google Scholar]
  45. Wright P. F., Karron R. A., Belshe R. B. & 15 other authors 2000; Evaluation of a live, cold-passaged, temperature-sensitive, respiratory syncytial virus vaccine candidate in infancy. J Infect Dis 182:1331–1342 [CrossRef]
     [Google Scholar]
  46. Zhang L., Peeples M. E., Boucher R. C., Collins P. L., Pickles R. J. 2002; Respiratory syncytial virus infection of human airway epithelial cells is polarized, specific to ciliated cells, and without obvious cytopathology. J Virol 76:5654–5666 [CrossRef]
     [Google Scholar]
  47. Zimmer G., Budz L., Herrler G. 2001; Proteolytic activation of respiratory syncytial virus fusion protein. J Biol Chem 276:31642–31650 [CrossRef]
     [Google Scholar]
  48. Zimmer G., Conzelmann K.-K., Herrler G. 2002; Cleavage at the furin consensus sequence RAK/KR109 and presence of the intervening peptide of the respiratory syncytial virus fusion protein are dispensable for virus replication in cell culture. J Virol 76:9218–9224 [CrossRef]
     [Google Scholar]
  49. Zimmer G., Rohn M., McGregor G. P., Schemann M., Conzelmann K. K., Herrler G. 2003; Virokinin, a bioactive peptide of the tachykinin family, is released from the fusion protein of bovine respiratory syncytial virus. J Biol Chem 278:46854–46861 [CrossRef]
     [Google Scholar]
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Bovine respiratory syncytial virus lacking the virokinin or with a mutation in furin cleavage site RA(R/K)R109 induces less pulmonary inflammation without impeding the induction of protective immunity in calves
J. Gen. Virol. 87, 1659 (2006); https://doi.org/10.1099/vir.0.81755-0
/content/journal/jgv/10.1099/vir.0.81755-0
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