Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Jul 1;100(1):226–233. doi: 10.1172/JCI119516

Respiratory syncytial virus infection results in airway hyperresponsiveness and enhanced airway sensitization to allergen.

J Schwarze 1, E Hamelmann 1, K L Bradley 1, K Takeda 1, E W Gelfand 1
PMCID: PMC508183  PMID: 9202075

Abstract

Viral respiratory infections can predispose to the development of asthma by mechanisms that are presently undetermined. Using a murine model of respiratory syncytial virus (RSV) infection, acute infection is associated with airway hyperresponsiveness as well as enhanced responses to subsequent sensitization to allergen. We demonstrate that acute viral infection results in increased airway responsiveness to inhaled methacholine and pulmonary neutrophilic and eosinophilic inflammation. This response is associated with predominant production of Th-1-type cytokines in peribronchial lymph node cells in vitro. Mice sensitized to ovalbumin via the airways after RSV infection developed increased airway responsiveness to methacholine and pulmonary eosinophilic and neutrophilic inflammation, associated with the predominant production of Th-2-type cytokines. Treatment of the mice with anti-IL-5 antibody abolished airway hyperresponsiveness and eosinophilic but not neutrophilic inflammation in both acutely infected mice and mice sensitized after infection. We conclude that RSV infection results in airway hyperresponsiveness in the acute phase and leads to changes in immune function that can enhance the effects of airway sensitization to antigen after infection. In both situations, airway hyperresponsiveness is closely associated with pulmonary eosinophilic inflammation. This model provides a means for further analyzing the influence of viral respiratory infections on airway sensitization and the development of altered airway responsiveness.

Full Text

The Full Text of this article is available as a PDF (197.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson J. J., Norden J., Saunders D., Toms G. L., Scott R. Analysis of the local and systemic immune responses induced in BALB/c mice by experimental respiratory syncytial virus infection. J Gen Virol. 1990 Jul;71(Pt 7):1561–1570. doi: 10.1099/0022-1317-71-7-1561. [DOI] [PubMed] [Google Scholar]
  2. Arnold R., Humbert B., Werchau H., Gallati H., König W. Interleukin-8, interleukin-6, and soluble tumour necrosis factor receptor type I release from a human pulmonary epithelial cell line (A549) exposed to respiratory syncytial virus. Immunology. 1994 May;82(1):126–133. [PMC free article] [PubMed] [Google Scholar]
  3. Arnold R., Werchau H., König W. Expression of adhesion molecules (ICAM-1, LFA-3) on human epithelial cells (A549) after respiratory syncytial virus infection. Int Arch Allergy Immunol. 1995 May-Jun;107(1-3):392–393. doi: 10.1159/000237049. [DOI] [PubMed] [Google Scholar]
  4. Bardin P. G., Johnston S. L., Pattemore P. K. Viruses as precipitants of asthma symptoms. II. Physiology and mechanisms. Clin Exp Allergy. 1992 Sep;22(9):809–822. doi: 10.1111/j.1365-2222.1992.tb02825.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Buckner C. K., Songsiridej V., Dick E. C., Busse W. W. In vivo and in vitro studies on the use of the guinea pig as a model for virus-provoked airway hyperreactivity. Am Rev Respir Dis. 1985 Aug;132(2):305–310. doi: 10.1164/arrd.1985.132.2.305. [DOI] [PubMed] [Google Scholar]
  6. Busse W. W. Respiratory infections: their role in airway responsiveness and the pathogenesis of asthma. J Allergy Clin Immunol. 1990 Apr;85(4):671–683. doi: 10.1016/0091-6749(90)90181-3. [DOI] [PubMed] [Google Scholar]
  7. Corry D. B., Folkesson H. G., Warnock M. L., Erle D. J., Matthay M. A., Wiener-Kronish J. P., Locksley R. M. Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J Exp Med. 1996 Jan 1;183(1):109–117. doi: 10.1084/jem.183.1.109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cypcar D., Stark J., Lemanske R. F., Jr The impact of respiratory infections on asthma. Pediatr Clin North Am. 1992 Dec;39(6):1259–1276. doi: 10.1016/s0031-3955(16)38444-9. [DOI] [PubMed] [Google Scholar]
  9. Empey D. W., Laitinen L. A., Jacobs L., Gold W. M., Nadel J. A. Mechanisms of bronchial hyperreactivity in normal subjects after upper respiratory tract infection. Am Rev Respir Dis. 1976 Feb;113(2):131–139. doi: 10.1164/arrd.1976.113.2.131. [DOI] [PubMed] [Google Scholar]
  10. Folkerts G., Van Esch B., Janssen M., Nijkamp F. P. Virus-induced airway hyperresponsiveness in guinea pigs in vivo: study of broncho-alveolar cell number and activity. Eur J Pharmacol. 1992 Dec 1;228(4):219–227. doi: 10.1016/0926-6917(92)90033-9. [DOI] [PubMed] [Google Scholar]
  11. Folkerts G., Verheyen A., Nijkamp F. P. Viral infection in guinea pigs induces a sustained non-specific airway hyperresponsiveness and morphological changes of the respiratory tract. Eur J Pharmacol. 1992 Sep 1;228(2-3):121–130. doi: 10.1016/0926-6917(92)90021-4. [DOI] [PubMed] [Google Scholar]
  12. Foster P. S., Hogan S. P., Ramsay A. J., Matthaei K. I., Young I. G. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J Exp Med. 1996 Jan 1;183(1):195–201. doi: 10.1084/jem.183.1.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Freihorst J., Piedra P. A., Okamoto Y., Ogra P. L. Effect of respiratory syncytial virus infection on the uptake of and immune response to other inhaled antigens. Proc Soc Exp Biol Med. 1988 Jun;188(2):191–197. doi: 10.3181/00379727-188-42727. [DOI] [PubMed] [Google Scholar]
  14. Frick O. L., German D. F., Mills J. Development of allergy in children. I. Association with virus infections. J Allergy Clin Immunol. 1979 Apr;63(4):228–241. doi: 10.1016/0091-6749(79)90106-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gern J. E., Vrtis R., Kelly E. A., Dick E. C., Busse W. W. Rhinovirus produces nonspecific activation of lymphocytes through a monocyte-dependent mechanism. J Immunol. 1996 Aug 15;157(4):1605–1612. [PubMed] [Google Scholar]
  16. Gershwin L. J., Himes S. R., Dungworth D. L., Giri S. N., Friebertshauser K. E., Camacho M. Effect of bovine respiratory syncytial virus infection on hypersensitivity to inhaled Micropolyspora faeni. Int Arch Allergy Immunol. 1994 May;104(1):79–91. doi: 10.1159/000236712. [DOI] [PubMed] [Google Scholar]
  17. Graham B. S., Bunton L. A., Wright P. F., Karzon D. T. Role of T lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice. J Clin Invest. 1991 Sep;88(3):1026–1033. doi: 10.1172/JCI115362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hamelmann E., Oshiba A., Loader J., Larsen G. L., Gleich G., Lee J., Gelfand E. W. Antiinterleukin-5 antibody prevents airway hyperresponsiveness in a murine model of airway sensitization. Am J Respir Crit Care Med. 1997 Mar;155(3):819–825. doi: 10.1164/ajrccm.155.3.9117011. [DOI] [PubMed] [Google Scholar]
  19. Holt P. G., Vines J., Bilyk N. Effect of influenza virus infection on allergic sensitization to inhaled antigen in mice. Int Arch Allergy Appl Immunol. 1988;86(1):121–123. doi: 10.1159/000234617. [DOI] [PubMed] [Google Scholar]
  20. Kudlacz E. M., Knippenberg R. W. Parainfluenza virus type-3 infection attenuates the respiratory effects of antigen challenge in sensitized guinea pigs. Inflamm Res. 1995 Mar;44(3):105–110. doi: 10.1007/BF01782019. [DOI] [PubMed] [Google Scholar]
  21. Lapin C. D., Hiatt P. W., Langston C., Mason E., Piedra P. T. A lamb model for human respiratory syncytial virus infection. Pediatr Pulmonol. 1993 Mar;15(3):151–156. doi: 10.1002/ppul.1950150305. [DOI] [PubMed] [Google Scholar]
  22. Larsen G. L., Renz H., Loader J. E., Bradley K. L., Gelfand E. W. Airway response to electrical field stimulation in sensitized inbred mice. Passive transfer of increased responsiveness with peribronchial lymph nodes. J Clin Invest. 1992 Mar;89(3):747–752. doi: 10.1172/JCI115651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Leibovitz E., Freihorst J., Piedra P. A., Ogra P. L. Modulation of systemic and mucosal immune responses to inhaled ragweed antigen in experimentally induced infection with respiratory syncytial virus implication in virally induced allergy. Int Arch Allergy Appl Immunol. 1988;86(1):112–116. doi: 10.1159/000234615. [DOI] [PubMed] [Google Scholar]
  24. McIntosh K., Ellis E. F., Hoffman L. S., Lybass T. G., Eller J. J., Fulginiti V. A. The association of viral and bacterial respiratory infections with exacerbations of wheezing in young asthmatic children. J Pediatr. 1973 Apr;82(4):578–590. doi: 10.1016/S0022-3476(73)80582-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Noah T. L., Becker S. Respiratory syncytial virus-induced cytokine production by a human bronchial epithelial cell line. Am J Physiol. 1993 Nov;265(5 Pt 1):L472–L478. doi: 10.1152/ajplung.1993.265.5.L472. [DOI] [PubMed] [Google Scholar]
  26. Openshaw P. J. Immunity and immunopathology to respiratory syncytial virus. The mouse model. Am J Respir Crit Care Med. 1995 Oct;152(4 Pt 2):S59–S62. doi: 10.1164/ajrccm/152.4_Pt_2.S59. [DOI] [PubMed] [Google Scholar]
  27. Oshiba A., Hamelmann E., Takeda K., Bradley K. L., Loader J. E., Larsen G. L., Gelfand E. W. Passive transfer of immediate hypersensitivity and airway hyperresponsiveness by allergen-specific immunoglobulin (Ig) E and IgG1 in mice. J Clin Invest. 1996 Mar 15;97(6):1398–1408. doi: 10.1172/JCI118560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Prince G. A., Jenson A. B., Horswood R. L., Camargo E., Chanock R. M. The pathogenesis of respiratory syncytial virus infection in cotton rats. Am J Pathol. 1978 Dec;93(3):771–791. [PMC free article] [PubMed] [Google Scholar]
  29. Reuman P. D., Keely S. P., Schiff G. M. Comparison of class and subclass antibody response to live and UV-inactivated RSV administered intranasally in mice. J Med Virol. 1991 Nov;35(3):198–205. doi: 10.1002/jmv.1890350310. [DOI] [PubMed] [Google Scholar]
  30. Reuman P. D., Keely S. P., Schiff G. M. Rapid recovery in mice after combined nasal/oral immunization with killed respiratory syncytial virus. J Med Virol. 1990 Sep;32(1):67–72. doi: 10.1002/jmv.1890320112. [DOI] [PubMed] [Google Scholar]
  31. Riedel F., Krause A., Slenczka W., Rieger C. H. Parainfluenza-3-virus infection enhances allergic sensitization in the guinea-pig. Clin Exp Allergy. 1996 May;26(5):603–609. [PubMed] [Google Scholar]
  32. Sakamoto M., Ida S., Takishima T. Effect of influenza virus infection on allergic sensitization to aerosolized ovalbumin in mice. J Immunol. 1984 May;132(5):2614–2617. [PubMed] [Google Scholar]
  33. Schumacher J. H., O'Garra A., Shrader B., van Kimmenade A., Bond M. W., Mosmann T. R., Coffman R. L. The characterization of four monoclonal antibodies specific for mouse IL-5 and development of mouse and human IL-5 enzyme-linked immunosorbent. J Immunol. 1988 Sep 1;141(5):1576–1581. [PubMed] [Google Scholar]
  34. Sigurs N., Bjarnason R., Sigurbergsson F., Kjellman B., Björkstén B. Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: a prospective cohort study with matched controls. Pediatrics. 1995 Apr;95(4):500–505. [PubMed] [Google Scholar]
  35. Toms G. L., Gardner P. S., Pullan C. R., Scott M., Taylor C. Secretion of respiratory syncytial virus inhibitors and antibody in human milk throughout lactation. J Med Virol. 1980;5(4):351–360. doi: 10.1002/1096-9071(1980)5:4<351::aid-jmv1890050412>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
  36. van Oosterhout A. J., van Ark I., Folkerts G., van der Linde H. J., Savelkoul H. F., Verheyen A. K., Nijkamp F. P. Antibody to interleukin-5 inhibits virus-induced airway hyperresponsiveness to histamine in guinea pigs. Am J Respir Crit Care Med. 1995 Jan;151(1):177–183. doi: 10.1164/ajrccm.151.1.7812550. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES