Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Transient cross-reactive immune responses can orchestrate antigenic variation in malaria

Abstract

The malaria parasite Plasmodium falciparum has evolved to prolong its duration of infection by antigenic variation of a major immune target on the surface of the infected red blood cell. This immune evasion strategy depends on the sequential, rather than simultaneous, appearance of immunologically distinct variants. Although the molecular mechanisms by which a single organism switches between variants are known in part1,2,3, it remains unclear how an entire population of parasites within the host can synchronize expression to avoid rapidly exhausting the variant repertoire. Here we show that short-lived, partially cross-reactive immune responses to parasite-infected erythrocyte surface antigens can produce a cascade of sequentially dominant antigenic variants, each of which is the most immunologically distinct from its preceding types. This model reconciles several previously unexplained and apparently conflicting epidemiological observations by demonstrating that individuals with stronger cross-reactive immune responses can, paradoxically, be more likely to sustain chronic infections. Antigenic variation has always been seen as an adaptation of the parasite to evade host defence: we show that the coordination necessary for the success of this strategy might be provided by the host.

This is a preview of subscription content

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: Dynamics of antigenic variants.
Figure 2: Dynamics of immune response.
Figure 3: Dependence of dynamics on efficacy of cross-reactive immune response.
Figure 4: Dependence of duration of infection on efficacy of cross-reactive immune response.

References

  1. 1

    Newbold, C. Antigenic variation in Plasmodium falciparum: mechanisms and consequences. Curr. Opin. Microbiol. 2, 420–425 (1999)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Scherf, A. et al. Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum. EMBO J. 17, 5418–5426 (1998)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Deitsch, K. W., Calderwood, M. S. & Wellems, T. E. Malaria. Cooperative silencing elements in var genes. Nature 412, 875–876 (2001)

    ADS  CAS  Article  PubMed  Google Scholar 

  4. 4

    Bull, P. C. et al. Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria. Nature Med. 4, 358–360 (1998)

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Giha, H. A. et al. Antibodies to variable Plasmodium falciparum-infected erythrocytes surface antigens are associated with protection from novel malaria infections. Immunol. Lett. 71, 117–126 (2000)

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Dodoo, D. et al. Antibodies to variant antigens on the surfaces of infected erythrocytes are associated with protection from malaria in Ghanian children. Infect. Immun. 69, 3713–3718 (2001)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Tebo, A. E., Kremsner, P. G., Piper, K. P. & Luty, A. J. Low antibody responses to variant surface antigens of Plasmodium falciparum are associated with severe malaria and increased susceptibility to malaria attacks in Gabonese children. Am. J. Trop. Med. Hyg. 67, 597–603 (2002)

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Marsh, K. & Howard, R. Antigens induced on erythrocytes by P. falciparum: expression of diverse and conserved determinants. Science 231, 150–153 (1986)

    ADS  CAS  Article  PubMed  Google Scholar 

  9. 9

    Gupta, S., Trenholme, K., Anderson, R. M. & Day, K. P. Antigenic diversity and the transmission dynamics of Plasmodium falciparum. Science 263, 961–963 (1994)

    ADS  CAS  Article  PubMed  Google Scholar 

  10. 10

    Bull, P. C., Lowe, B. S., Kortok, M. & Marsh, K. Antibody recognition of Plasmodium falciparum erythrocyte surface antigens in Kenya: evidence for rare and prevalent variants. Infect. Immun. 67, 733–739 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Ofori, M. F. et al. Malaria-induced acquisition of antibodies to Plasmodium falciparum variant surface antigens. Infect. Immun. 70, 2982–2988 (2002)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Giha, H. A. et al. Nine-year longitudinal study of antibodies to variant antigens on the surface of Plasmodium falciparum-infected erythrocytes. Infect. Immun. 67, 4092–4098 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Kinyanjui, S., Bull, P. C., Newbold, C. I. & Marsh, K. Kinetics of antibody responses to Plasmodium falciparum-infected erythrocyte variant surface antigens. J. Infect. Dis. 187, 667–674 (2003)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Bull, P. C. et al. Plasmodium falciparum infections are associated with agglutinating antibodies to parasite-infected erythrocyte surface antigens among healthy Kenyan children. J. Infect. Dis. 185, 1688–1691 (2002)

    Article  Google Scholar 

  15. 15

    Kosinski, R. J. Antigenic variation in trypanosomes: a computer analysis of variant order. Parasitology 80, 343–357 (1980)

    CAS  Article  Google Scholar 

  16. 16

    Agur, Z., Abiri, D. & Van der Ploeg, L. H. T. Ordered appearance of antigenic variants of African trypanosomes explained in a mathematical model based on a stochastic switch process and immune-selection against putative switch intermediates. Proc. Natl Acad. Sci. USA 86, 9626–9630 (1989)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Frank, S. A. A model for the sequential dominance of antigenic variants in African trypanosome infections. Proc. R. Soc. Lond. B 266, 1397–1401 (1999)

    CAS  Article  Google Scholar 

  18. 18

    Antia, R., Nowak, M. A. & Anderson, R. M. Antigenic variation and the within-host dynamics of parasites. Proc. Natl Acad. Sci. USA 93, 985–989 (1996)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Nowak, M. A. et al. Antigenic oscillations and shifting immunodominance in HIV-1 infections. Nature 375, 606–611 (1995)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Haraguchi, Y. & Sasaki, A. Evolutionary pattern of intra-host pathogen antigenic drift: effect of cross-reactivity in immune response. Phil. Trans. R. Soc. Lond. B 352, 11–20 (1997)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Gog, J. R. & Grenfell, B. Dynamics and selection of many-strain pathogens. Proc. Natl Acad. Sci. USA 99, 17209–17214 (2002)

    ADS  CAS  Article  PubMed  Google Scholar 

  22. 22

    Molineaux, L. et al. Plasmodium falciparum parasitaemia described by a new mathematical model. Parasitology 122, 379–391 (2001)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Paget-McNichol, S., Gatton, M., Hastings, I. & Saul, A. The Plasmodium falciparum var gene switching rate, switching mechanism and patterns of parasite recrudenscence described by mathematical modelling. Parasitology 124, 225–235 (2002)

    Google Scholar 

  24. 24

    Gupta, S. et al. The maintenance of strain structure in populations of recombining infectious agents. Nature Med. 2, 437–442

  25. 25

    Chattopadhyay, R. et al. Plasmodium falciparum infection elicits both variant-specific and cross-reactive antibodies against variant surface antigens. Infect. Immun. 71, 597–604 (2003)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Gamain, B., Miller, L. H. & Baruch, D. I. The surface variant antigens of Plasmodium falciparum contain cross-reactive epitopes. Proc. Natl Acad. Sci. USA 98, 2664–2669 (2001)

    ADS  CAS  Article  PubMed  Google Scholar 

  27. 27

    Molineaux, L. & Gramiccia, G. The Garki Project (World Health Organisation, Geneva, 1980)

    Google Scholar 

  28. 28

    Beck, H.-P. et al. Analysis of multiple Plasmodium falciparum infections in Tanzanian children during the trial of the malaria vaccine SPf66. J. Infect. Dis. 175, 921–926 (1997)

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank A. McLean, G. Rudenko and D. Barry for their valuable comments, and the MRC and The Wellcome Trust for financial support.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Sunetra Gupta.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure 1

The effect of explicitly incorporating clonal expansion of immune cells.

Supplementary Figure 1 Legend

Containing details of modified equations.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Recker, M., Nee, S., Bull, P. et al. Transient cross-reactive immune responses can orchestrate antigenic variation in malaria. Nature 429, 555–558 (2004). https://doi.org/10.1038/nature02486

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing