Pegylated interferon-α protects type 1 pneumocytes against SARS coronavirus infection in macaques

Abstract

The primary cause of severe acute respiratory syndrome (SARS) is a newly discovered coronavirus1,2,3,4,5,6,7. Replication of this SARS coronavirus (SCV) occurs mainly in the lower respiratory tract, and causes diffuse alveolar damage2,7,8. Lack of understanding of the pathogenesis of SARS has prevented the rational development of a therapy against this disease. Here we show extensive SCV antigen expression in type 1 pneumocytes of experimentally infected cynomolgus macaques (Macaca fascicularis) at 4 d postinfection (d.p.i.), indicating that this cell type is the primary target for SCV infection early in the disease, and explaining the subsequent pulmonary damage. We also show that prophylactic treatment of SCV-infected macaques with the antiviral agent pegylated interferon-α (IFN-α) significantly reduces viral replication and excretion, viral antigen expression by type 1 pneumocytes and pulmonary damage, compared with untreated macaques. Postexposure treatment with pegylated IFN-α yielded intermediate results. We therefore suggest that pegylated IFN-α protects type 1 pneumocytes from SCV infection, and should be considered a candidate drug for SARS therapy

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Histological lesions and immunohistochemical and ultrastructural detection of SCV in lungs of experimentally infected macaques.
Figure 2: Antiviral activity of pegylated IFN-α against SCV in vitro and its biological activity in macaques.
Figure 3: Effect of pegylated IFN-α on SCV excretion in macaques.
Figure 4: Effect of pegylated IFN-α on SCV replication, viral antigen expression and histological lesions in lungs of SCV-infected macaques at 4 d.p.i.

References

  1. 1

    Fouchier, R.A.M. et al. Koch's postulates fulfilled for SARS virus. Nature 423, 240 (2003).

  2. 2

    Kuiken, T. et al. Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet 362, 263–270 (2003).

  3. 3

    Marra, M.A. et al. The genome sequence of the SARS-associated coronavirus. Science 300, 1399–1404 (2003).

  4. 4

    Rota, P.A. et al. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science 300, 1394–1399 (2003).

  5. 5

    Drosten, C. et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N. Engl. J. Med. 348, 1967–1976 (2003).

  6. 6

    Ksiazek, T.G. et al. A novel coronavirus associated with severe acute respiratory syndrome. N. Engl. J. Med. 348, 1953–1966 (2003).

  7. 7

    Peiris, J.S.M. et al. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 361, 1319–1325 (2003).

  8. 8

    Tsang, K.W. et al. A cluster of cases of severe acute respiratory syndrome in Hong Kong. N. Engl. J. Med. 348, 1977–1985 (2003).

  9. 9

    Lee, N. et al. A major outbreak of severe acute respiratory syndrome in Hong Kong. N. Engl. J. Med. 348, 1986–1994 (2003).

  10. 10

    Poutanen, S.M. et al. Identification of severe acute respiratory syndrome in Canada. N. Engl. J. Med. 348, 1995–2005 (2003).

  11. 11

    Nicholls, J.M. et al. Lung pathology of fatal severe acute respiratory syndrome. Lancet 361, 1773–1178 (2003).

  12. 12

    Ware, L.B. & Matthay, M.A. The acute respiratory distress syndrome. N. Engl. J. Med. 342, 1334–1349 (2000).

  13. 13

    Williams, M.C. The alveolar epithelium: structure and study by immunohistochemistry. in Electron Microscopy of the Lung (ed. Schraufnagel, D.E.) 121–147 (Marcel Dekker, New York, 1990).

  14. 14

    Bellum, S.C. et al. Respiratory reovirus 1/L induction of intraluminal fibrosis. A model for the study of bronchiolitis obliterans organizing pneumonia. Am. J. Pathol. 150, 2243–2254 (1997).

  15. 15

    London, L. et al. Respiratory reovirus 1/L induction of diffuse alveolar damage: pulmonary fibrosis is not modulated by corticosteroids in acute respiratory distress syndrome in mice. Clin. Immunol. 103, 284–295 (2002).

  16. 16

    Pei, J., Sekellick, M.J., Marcus, P.I., Choi, I.S. & Collisson, E.W. Chicken interferon type I inhibits infectious bronchitis virus replication and associated respiratory illness. J. Interferon Cytokine Res. 21, 1071–1077 (2001).

  17. 17

    Smith, A.L., Barthold, S.W. & Beck, D.S. Intranasally administered α/β interferon prevents extension of mouse hepatitis virus, strain JHM, into the brains of BALB/cByJ mice Ant. Res. 8, 239–245 (1987).

  18. 18

    Turner, R.B., Felton, A., Kosak, K., Kelsey, D.K. & Meschievitz, C.K. Prevention of experimental coronavirus colds with intranasal α-2b interferon. J. Infect. Dis. 154, 443–447 (1986).

  19. 19

    Manns, M.P. et al. Peginterferon α-2b plus ribavirin compared with interferon α-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358, 958–965 (2001).

  20. 20

    Cinatl, J. et al. Treatment of SARS with human interferons. Lancet 362, 293–294 (2003).

  21. 21

    Bukowski, R.M. et al. Treating cancer with PEG Intron: pharmacokinetic profile and dosing guidelines for an improved interferon-α2b formulation. Cancer 95, 389–396 (2002).

  22. 22

    Van Gool, A.R. et al. Serum amino acids, biopterin and neopterin during long-term immunotherapy with interferon-α in high-risk melanoma patients. Psychiatry Res. 119, 125–132 (2003).

  23. 23

    Franks, T.J. et al. Lung pathology of severe acute respiratory syndrome (SARS): a study of 8 autopsy cases from Singapore. Hum. Pathol. 34, 743–748 (2003).

  24. 24

    Bedrossian, C.W., Sussman, J., Conklin, R.H. & Kahan, B. Azathioprine-associated interstitial pneumonitis. Am. J. Clin. Path. 82, 148–154 (1984).

  25. 25

    Biron, C.A. Interferons α and β as immune regulators: a new look. Immunity 14, 661–664 (2001).

  26. 26

    Finter, N.B. & Oldham, R.K. (eds.) Interferons: In Vivo and Clinical Studies. Vol. 4 (Elsevier, Amsterdam, 1985).

  27. 27

    Booth, C.M. et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA 289, 2801–2809 (2003).

  28. 28

    Peiris, J.S.M. et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet 361, 1767–1772 (2003).

  29. 29

    Fouchier, R.A. et al. Detection of influenza viruses from different species by PCR amplification of conserved sequences in the matrix gene. J. Clin. Microbiol. 38, 4096–5001 (2000).

Download references

Acknowledgements

We thank S. Bruijns, J.M. Vrolijk, G. Aron, F. van der Panne, R. Dias d'Ullois and D. Fekkes for assistance, and J.D. Laman for advice on immunohistochemistry.

Author information

Correspondence to Albert D M E Osterhaus.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Haagmans, B., Kuiken, T., Martina, B. et al. Pegylated interferon-α protects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat Med 10, 290–293 (2004). https://doi.org/10.1038/nm1001

Download citation

Further reading