Role of deficient type III interferon-λ production in asthma exacerbations

Abstract

Rhinoviruses are the major cause of asthma exacerbations, and asthmatics have increased susceptibility to rhinovirus and risk of invasive bacterial infections. Here we show deficient induction of interferon-λs by rhinovirus in asthmatic primary bronchial epithelial cells and alveolar macrophages, which was highly correlated with severity of rhinovirus-induced asthma exacerbation and virus load in experimentally infected human volunteers. Induction by lipopolysaccharide in asthmatic macrophages was also deficient and correlated with exacerbation severity. These results identify previously unknown mechanisms of susceptibility to infection in asthma and suggest new approaches to prevention and/or treatment of asthma exacerbations.

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Figure 1: Deficient IFN-λ production in primary human bronchial epithelial cells from asthmatic compared to normal subjects and relationship to increased rhinovirus replication in vitro.
Figure 2: Deficient rhinovirus- and lipopolysaccharide-induced IFN-λ production from bronchoalveolar lavage cells from asthmatic compared to normal subjects and relationships to illness severity, airway inflammation and virus load in vivo.

References

  1. 1

    Corne, J.M. et al. Lancet 359, 831–834 (2002).

  2. 2

    Talbot, T.R. et al. N. Engl. J. Med. 352, 2082–2090 (2005).

  3. 3

    Wark, P. et al. J. Exp. Med. 201, 937–947 (2005).

  4. 4

    Kotenko, S.V. et al. Nat. Immunol. 4, 69–77 (2003).

  5. 5

    Sheppard, P. et al. Nat. Immunol. 4, 63–68 (2003).

  6. 6

    Spann, K.M., Tran, K.C., Chi, B., Rabin, R.L. & Collins, P.L. J. Virol. 78, 4363–4369 (2004).

  7. 7

    Johnston, S.L. et al. Br. Med. J. 310, 1225–1229 (1995).

  8. 8

    Johnston, S.L. et al. N. Engl. J. Med. 354, 1589–1600 (2006).

  9. 9

    Yoneyama, M. et al. Nat. Immunol. 5, 730–737 (2004).

  10. 10

    Carr, D.J., Tomanek, L., Silverman, R.H., Campbell, I.L. & Williams, B.R. J. Virol. 79, 9341–9345 (2005).

  11. 11

    Yang, K. et al. Immunity 23, 465–478 (2005).

  12. 12

    Hewson, C.A., Jardine, A., Edwards, M.R., Laza-Stanca, V. & Johnston, S.L. J. Virol. 79, 12273–12279 (2005).

  13. 13

    Fitzgerald, K.A. et al. J. Exp. Med. 198, 1043–1055 (2003).

  14. 14

    Illi, S. et al. Br. Med. J. 322, 390–395 (2001).

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Acknowledgements

M.C. was the recipient of a European Respiratory Society fellowship (LTRF2003-017). P.A.B.W. was supported by the National Health and Medical Research Council Australia Neil Hamilton Fairley Fellowship. This work was supported by the Medical Research Council, UK: Clinical Research Professorship (to S.T.H.) & Clinical Research Fellowship (to S.D.M. and S.L.J.), British Medical Association HC Roscoe Fellowships (to P.A.B.W. and S.D.M.), Asthma UK grant numbers 05/067 (to S.L.J.) and 03/031 (to P.A.B.W., D.E.D. and S.T.H.), United States Public Health Services Grants AI051139 and AI057468 from the National Institute of Allergy and Infectious Diseases (to S.V.K.) and by British Lung Foundation/Severin Wunderman Family Foundation Programme Grant 00/02 (to S.L.J.).

Author information

M.C. performed all the laboratory work (except where stated performed by others) and statistical analyses and wrote the first draft of the manuscript. S.D.M. performed all the patient recruitment for both the monocyte studies and the human experimental infection studies and performed the human infection study. V.L.-S. performed the monocyte-derived macrophage experiments and assisted with the rest of the studies. M.R.E. designed the IFN-λ quantitative PCRs and assisted with the rest of the studies. P.A.B.W. performed the patient recruitment and carried out the primary bronchial epithelial cell infection studies. N.W.B., T.K., P.M., L.A.S., H.L.P., L.S. and A.L.-A. assisted with the studies. O.M.K. assisted in the patient recruitment and clinical conduct of the studies. S.T.H. and D.E.D. supervised and assisted in the conduct of the primary bronchial infection study. S.V.K. advised on the scientific aspects of the IFN-λ studies and provided reagents. A.P. co-supervised the work of M.C. S.L.J. conceived, designed and supervised all the studies, wrote the final draft of the manuscript and acts as guarantor for the studies. All authors contributed to the writing of the manuscript and have approved the final version for publication.

Correspondence to Sebastian L Johnston.

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Competing interests

Stephen T. Holgate and Donna E. Davies were cofounders of, hold shares in and are consultants for, and Sebastian L. Johnston is a consultant for Synairgen PLC, which has an interest in developing interferons for treating respiratory diseases. Sebastian L. Johnston, Stephen T. Holgate, Donna E. Davies, Peter A.B. Wark and Sergei V. Kotenko are inventors on patents relating to the use of interferons for treating respiratory diseases.

Supplementary information

Supplementary Fig. 1

IFN-λs are induced by rhinovirus infection of bronchial epithelial cells, monocytes and macrophages. (PDF 810 kb)

Supplementary Fig. 2

IFN-λs induce IFN-stimulated genes in and protect bronchial epithelial cells against rhinovirus infection in vitro. (PDF 636 kb)

Supplementary Table 1

Demographic data for patients entering the clinical studies. (PDF 45 kb)

Supplementary Methods (PDF 154 kb)

Supplementary Note (PDF 158 kb)

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