Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes

Abstract

Pandemic influenza viruses often cause severe disease in middle-aged adults without preexisting comorbidities. The mechanism of illness associated with severe disease in this age group is not well understood1,2,3,4,5,6,7,8,9,10. Here we find preexisting serum antibodies that cross-react with, but do not protect against, 2009 H1N1 influenza virus in middle-aged adults. Nonprotective antibody is associated with immune complex–mediated disease after infection. We detected high titers of serum antibody of low avidity for H1-2009 antigen, and low-avidity pulmonary immune complexes against the same protein, in severely ill individuals. Moreover, C4d deposition—a marker of complement activation mediated by immune complexes—was present in lung sections of fatal cases. Archived lung sections from middle-aged adults with confirmed fatal influenza 1957 H2N2 infection revealed a similar mechanism of illness. These observations provide a previously unknown biological mechanism for the unusual age distribution of severe cases during influenza pandemics.

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: Histopathology and virus titers in 2009 H1N1 disease.
Figure 2: Inflammation in influenza A 2009 H1N1 disease.
Figure 3: Lymphopenia in influenza A 2009 H1N1 disease.
Figure 4: Immune complex–mediated disease in 2009 H1N1 influenza infection.

References

  1. 1

    Morens, D.M., Taubenberger, J.K. & Fauci, A.S. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. J. Infect. Dis. 198, 962–970 (2008).

  2. 2

    Tumpey, T.M. et al. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 310, 77–80 (2005).

  3. 3

    Itoh, Y. et al. In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses. Nature 460, 1021–1025 (2009).

  4. 4

    Kobasa, D. et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 445, 319–323 (2007).

  5. 5

    Geiss, G.K. et al. Cellular transcriptional profiling in influenza A virus–infected lung epithelial cells: the role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza. Proc. Natl. Acad. Sci. USA 99, 10736–10741 (2002).

  6. 6

    Kash, J.C. et al. Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus. Nature 443, 578–581 (2006).

  7. 7

    Taubenberger, J.K. & Morens, D.M. 1918 influenza: the mother of all pandemics. Emerg. Infect. Dis. 12, 15–22 (2006).

  8. 8

    Simonsen, L. et al. Pandemic versus epidemic influenza mortality: a pattern of changing age distribution. J. Infect. Dis. 178, 53–60 (1998).

  9. 9

    Morens, D.M. & Fauci, A.S. The 1918 influenza pandemic: insights for the 21st century. J. Infect. Dis. 195, 1018–1028 (2007).

  10. 10

    Perez-Padilla, R. et al. Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico. N. Engl. J. Med. 361, 680–689 (2009).

  11. 11

    Chowell, G. et al. Severe respiratory disease concurrent with the circulation of H1N1 influenza. N. Engl. J. Med. 361, 674–679 (2009).

  12. 12

    Hancock, K. et al. Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus. N. Engl. J. Med. 361, 1945–1952 (2009).

  13. 13

    Centers for Disease Control and Prevention (CDC). Serum cross-reactive antibody response to a novel influenza A (H1N1) virus after vaccination with seasonal influenza vaccine. MMWR Morb. Mortal. Wkly. Rep. 58, 521–524 (2009).

  14. 14

    The ANZIC Influenza Investigators. Critical care services and 2009 H1N1 influenza in Australia and New Zealand. N. Engl. J. Med. 361, 1925–1934 (2009).

  15. 15

    Bhat, N. et al. Influenza-associated deaths among children in the United States, 2003–2004. N. Engl. J. Med. 353, 2559–2567 (2005).

  16. 16

    Thompson, W.W. et al. Influenza-associated hospitalizations in the United States. J. Am. Med. Assoc. 292, 1333–1340 (2004).

  17. 17

    Delgado, M.F. et al. Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease. Nat. Med. 15, 34–41 (2009).

  18. 18

    Reichert, T., Chowell, G., Nishiura, H., Christensen, R.A. & McCullers, J.A. Does glycosylation as a modifier of original antigenic sin explain the case age distribution and unusual toxicity of pandemic novel H1N1 influenza? BMC Infect. Dis. 10, 5 (2010).

  19. 19

    Mauad, T. et al. Lung pathology in fatal novel human influenza A (H1N1) infection. Am. J. Resp. Crit. Care. Med. 181, 72–79 (2010).

  20. 20

    Kobasa, D. et al. Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus. Nature 431, 703–707 (2004).

  21. 21

    Perrone, L.A., Plowden, J.K., García-Sastre, A., Katz, J.M. & Tumpey, T.M. H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog. 4, e1000115 (2008).

  22. 22

    de Jong, M.D. et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat. Med. 12, 1203–1207 (2006).

  23. 23

    Lewis, D.E., Gilbert, B.E. & Knight, V. Influenza virus infection induces functional alterations in peripheral blood lymphocytes. J. Immunol. 137, 3777–3781 (1986).

  24. 24

    Greenbaum, J.A. et al. Preexisting immunity against swine-origin H1N1 influenza viruses in the general human population. Proc. Natl. Acad. Sci. USA 106, 20365–20370 (2009).

  25. 25

    Johnson, T.R. et al. Priming with secreted glycoprotein G of respiratory syncytial virus (RSV) augments interleukin-5 production and tissue eosinophilia after RSV challenge. J. Virol. 72, 2871–2880 (1998).

  26. 26

    Polack, F.P. et al. A Role for immune complexes in enhanced respiratory syncytial virus disease. J. Exp. Med. 196, 859–865 (2002).

  27. 27

    Regele, H. et al. Endothelial C4d deposition is associated with inferior kidney allograft outcome independently of cellular rejection. Nephrol. Dial. Transplant. 16, 2058–2066 (2001).

  28. 28

    Hall, C.B., Douglas, R.G., Simons, R.L. & Geiman, J.M. Interferon production in children with respiratory syncytial, influenza and parainfluenza virus infections. J. Pediatr. 93, 28–32 (1978).

  29. 29

    Salomon, R., Hoffmann, E. & Webster, R.G. Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection. Proc. Natl. Acad. Sci. USA 104, 12479–12481 (2007).

  30. 30

    Palacios, G. et al. Streptococcus pneumoniae coinfection is correlated with the severity of H1N1 pandemic influenza. PLoS ONE 4, e8540 (2009).

Download references

Acknowledgements

Funded by the Fundacion INFANT 2008 Fundraising Campaign and AI-054952 (F.P.P.), the Thrasher Research Fund Early Career Award and Fogarty International Center International Clinical Research Fellows Program at Vanderbilt (R24 TW007988) (G.A.M. and J.P.B.), US Department of Defense grant HDTRA1-08-10-BRCWMD-BAA and US National Institutes of Health grant P01 AI058113 (J.E.C. Jr.). Doctoral awards from the Consejo Nacional de Investigaciones Cientıficas y Técnicas, Argentina (A.C.M. and J.P.B.).

Author information

F.P.P., G.A.M., K.M.E., J.D.C., J.E.C. Jr., J.V.W., A.C.M., J.P.B. and M.F.L. designed the project. A.C.M., J.P.B., M.F.L., J.Z.H., B.M., L.D., K.P.W., J.V.W., G.A.M. and F.P.P. performed experiments. J.C.K., J.K., J.B., C.R., Le. A., L.D., R.L., V.S., E.B., Li. A., G.C., J.F., L.S., J.J., M.E., J.E.C. Jr. and J.V.W. developed or provided key reagents or contributed samples. F.P.P. supervised the project. A.C.M., J.P.B., M.F.L., K.M.E., J.D.C., G.A.M. and F.P.P. wrote the paper.

Correspondence to Guillermina A Melendi or Fernando P Polack.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 (PDF 633 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Monsalvo, A., Batalle, J., Lopez, M. et al. Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes. Nat Med 17, 195–199 (2011). https://doi.org/10.1038/nm.2262

Download citation

Further reading