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Endemic Burkitt's lymphoma: a polymicrobial disease?

Nature Reviews Microbiology volume 3, pages 182–187 (2005)Cite this article

Abstract

Endemic Burkitt's lymphoma is the most common childhood cancer in equatorial Africa. Two ubiquitous human pathogens are thought to be responsible for the aetiology of this disease: Epstein–Barr virus and Plasmodium falciparum malaria. New data suggest how these two pathogens might interact to result in disease and provide insights into the emerging concepts of polymicrobial disease pathogenesis.

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Figure 1: Child with Burkitt's lymphoma.
Figure 2: Biology of EBV infection in vivo.
Figure 3: Plasmodium falciparum interaction with EBV persistence and immunity.

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References

  1. Bakaletz, L. O. Developing animal models for polymicrobial diseases. Nature Rev. Microbiol. 2, 552–568 (2004).

    Article  CAS  Google Scholar 

  2. Brogden, K. in Polymicrobial Diseases (eds Brogden, K. & Guthmiller, J.) 3–20 (ASM Press, Washington DC, 2002).

    Google Scholar 

  3. Burkitt, D. P. Sarcoma involving jaws in African children. Brit. J. Surg. 46, 218–223 (1958).

    Article  CAS  Google Scholar 

  4. Fleming, A. F. The epidemiology of lymphomas and leukaemias in Africa — an overview. Leuk. Res. 9, 735–740 (1985).

    Article  CAS  Google Scholar 

  5. Biggar, R. J. et al. Primary Epstein–Barr virus infections in African infants. I. Decline of maternal antibodies and time of infection. Int. J. Cancer 22, 239–243. (1978).

    Article  CAS  Google Scholar 

  6. Henle, G. & Henle, W. Observations on childhood infections with the Epstein–Barr virus. J. Infect. Dis. 121, 303–310 (1970).

    Article  CAS  Google Scholar 

  7. Biggar, R. J. et al. Primary Epstein–Barr virus infections in African infants. II. Clinical and serological observations during seroconversion. Int. J. Cancer 22, 244–250 (1978).

    Article  CAS  Google Scholar 

  8. Geser, A., Brubaker, G. & Olwit, G. W. The frequency of Epstein–Barr virus infection and Burkitt's lymphoma at high and low altitudes in East Africa. Rev. Epidemiol. Sante Publique 28, 307–321 (1980).

    CAS  PubMed  Google Scholar 

  9. Moormann, A. et al. Exposure to holendemic malaria results in elevated Epstein–Barr viral loads in children. J. Infect. Dis. (in the press).

  10. Mbogo, C. N. et al. Relationships between Plasmodium falciparum transmission by vector populations and the incidence of severe disease at nine sites on the Kenyan coast. Am. J. Trop. Med. Hyg. 52, 201–206 (1995).

    Article  CAS  Google Scholar 

  11. Snow, R. W. et al. Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa. Lancet 349, 1650–1654 (1997).

    Article  CAS  Google Scholar 

  12. Bloland, P. B. et al. Longitudinal cohort study of the epidemiology of malaria infections in an area of intense malaria transmission II. Descriptive epidemiology of malaria infection and disease among children. Am. J. Trop. Med. Hyg. 60, 641–648 (1999).

    Article  CAS  Google Scholar 

  13. Miller, G. in Virology (eds Fields, B. N. et al.) 1921–1958 (Raven Press, New York, 1990).

    Google Scholar 

  14. Babcock, J. G., Hochberg, D. & Thorley-Lawson, A. D. The expression pattern of Epstein–Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity 13, 497–506 (2000).

    Article  CAS  Google Scholar 

  15. Joseph, A. M., Babcock, G. J. & Thorley-Lawson, D. A. Cells expressing the Epstein–Barr virus growth program are present in and restricted to the naive B-cell subset of healthy tonsils. J. Virol. 74, 9964–9971 (2000).

    Article  CAS  Google Scholar 

  16. Ehlin-Henriksson, B., Gordon, J. & Klein, G. B-lymphocyte subpopulations are equally susceptible to Epstein-Barr virus infection, irrespective of immunoglobulin isotype expression. Immunology 108, 427–430 (2003).

    Article  CAS  Google Scholar 

  17. Kuppers, R. B cells under influence: transformation of B cells by Epstein–Barr virus. Nature Rev. Immunol. 3, 801–812 (2003).

    Article  Google Scholar 

  18. Laichalk, L. L., Hochberg, D., Babcock, G. J., Freeman, R. B. & Thorley-Lawson, D. A. The dispersal of mucosal memory B cells: evidence from persistent EBV infection. Immunity 16, 745–754 (2002).

    Article  CAS  Google Scholar 

  19. Rose, C. et al. Pediatric solid-organ transplant recipients carry chronic loads of Epstein–Barr virus exclusively in the immunoglobulin D-negative B-cell compartment. J. Clin. Microbiol. 39, 1407–1415 (2001).

    Article  CAS  Google Scholar 

  20. Hochberg, D. et al. Demonstration of the Burkitt's lymphoma Epstein–Barr virus phenotype in dividing latently infected memory cells in vivo. Proc. Natl Acad. Sci. USA 101, 239–244 (2004).

    Article  CAS  Google Scholar 

  21. Rowe, M. et al. Differences in B cell growth phenotype reflect novel patterns of Epstein–Barr virus latent gene expression in Burkitt's lymphoma cells. EMBO J. 6, 2743–2751 (1987).

    Article  CAS  Google Scholar 

  22. Crawford, D. H. & Ando, I. EB virus induction is associated with B-cell maturation. Immunology 59, 405–409 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Rochford, R. & Mosier, D. E. Differential Epstein–Barr virus gene expression in B-cell subsets recovered from lymphomas in SCID mice after transplantation of human peripheral blood lymphocytes. J. Virol. 69, 150–155 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Khanna, R. & Burrows, S. R. Role of cytotoxic T lymphocytes in Epstein–Barr virus-associated diseases. Annu. Rev. Microbiol. 54, 19–48 (2000).

    Article  CAS  Google Scholar 

  25. Greenwood, B. M. Possible role of a B-cell mitogen in hyper γ-globulinaemia in malaria and trypanosomiasis. Lancet 1, 435–436 (1974).

    Article  CAS  Google Scholar 

  26. Kataaha, P. K., Facer, C. A., Mortazavi-Milani, S. M., Stierle, H. & Holborow, E. J. Stimulation of autoantibody production in normal blood lymphocytes by malaria culture supernatants. Parasite Immunol. 6, 481–492 (1984).

    Article  CAS  Google Scholar 

  27. Gabrielsen, A. A. Jr & Jensen, J. B. Mitogenic activity of extracts from continuous cultures of Plasmodium falciparum. Am. J. Trop. Med. Hyg. 31, 441–448 (1982).

    Article  Google Scholar 

  28. Greenwood, B. M., Oduloju, A. J. & Platts-Mills, T. A. Partial characterization of a malaria mitogen. Trans. R. Soc. Trop. Med. Hyg. 73, 178–182 (1979).

    Article  CAS  Google Scholar 

  29. Donati, D. et al. Identification of a polyclonal B-cell activator in Plasmodium falciparum. Infect. Immun. 72, 5412–5418 (2004).

    Article  CAS  Google Scholar 

  30. Pichyangkul, S. et al. Malaria blood-stage parasites activate human plasmacytoid dendritic cells and murine dendritic cells through a Toll-like receptor 9-dependent pathway. J. Immunol. 172, 4926–4933 (2004).

    Article  CAS  Google Scholar 

  31. Bernasconi, N. L., Onai, N. & Lanzavecchia, A. A role for Toll-like receptors in acquired immunity: upregulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells. Blood 101, 4500–4504 (2003).

    Article  CAS  Google Scholar 

  32. Bourke, E., Bosisio, D., Golay, J., Polentarutti, N. & Mantovani, A. The Toll-like receptor repertoire of human B lymphocytes: inducible and selective expression of TLR9 and TLR10 in normal and transformed cells. Blood 102, 956–963 (2003).

    Article  Google Scholar 

  33. Hornung, V. et al. Quantitative expression of Toll-like receptor 1–10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J. Immunol. 168, 4531–4537 (2002).

    Article  CAS  Google Scholar 

  34. He, B., Qiao, X. & Cerutti, A. CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10. J. Immunol. 173, 4479–4491 (2004).

    Article  CAS  Google Scholar 

  35. Kataaha, P. K., Facer, C. A. & Holborow, E. J. Plasmodium falciparum products enhance human lymphocyte transformation by Epstein–Barr virus. Clin. Exp. Immunol. 56, 371–376 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Lam, K. M., Syed, N., Whittle, H. & Crawford, D. H. Circulating Epstein–Barr virus-carrying B cells in acute malaria. Lancet 337, 876–878 (1991).

    Article  CAS  Google Scholar 

  37. Moss, D. J. et al. A comparison of Epstein–Barr virus-specific T-cell immunity in malaria-endemic and nonendemic regions of Papua New Guinea. Int. J. Cancer 31, 727–732 (1983).

    Article  CAS  Google Scholar 

  38. Whittle, H. C. et al. T-cell control of Epstein–Barr virus-infected B cells is lost during P. falciparum malaria. Nature 312, 449–450 (1984).

    Article  CAS  Google Scholar 

  39. Whittle, H. C. et al. The effects of Plasmodium falciparum malaria on immune control of B lymphocytes in Gambian children. Clin. Exp. Immunol. 80, 213–218 (1990).

    Article  CAS  Google Scholar 

  40. Brehm, M. A., Selin, L. K. & Welsh, R. M. CD8 T cell responses to viral infections in sequence. Cell. Microbiol. 6, 411–421 (2004).

    Article  CAS  Google Scholar 

  41. Wodarz, D. Cytotoxic T-lymphocyte memory, virus clearance and antigenic heterogeneity. Proc. R. Soc. Lond. B Biol. Sci. 268, 429–436 (2001).

    Article  CAS  Google Scholar 

  42. Liu, H. et al. Quantitative analysis of long-term virus-specific CD8+-T-cell memory in mice challenged with unrelated pathogens. J. Virol. 77, 7756–7763 (2003).

    Article  CAS  Google Scholar 

  43. Kim, S. K. & Welsh, R. M. Comprehensive early and lasting loss of memory CD8 T cells and functional memory during acute and persistent viral infections. J. Immunol. 172, 3139–3150 (2004).

    Article  CAS  Google Scholar 

  44. Blake, N. et al. Human CD8+ T-cell responses to EBV EBNA1: HLA class I presentation of the (Gly-Ala)-containing protein requires exogenous processing. Immunity 7, 791–802 (1997).

    Article  CAS  Google Scholar 

  45. Levitskaya, J. et al. Inhibition of antigen processing by the internal repeat region of the Epstein–Barr virus nuclear antigen-1. Nature 375, 685–688 (1995).

    Article  CAS  Google Scholar 

  46. Yin, Y., Manoury, B. & Fahraeus, R. Self-inhibition of synthesis and antigen presentation by Epstein–Barr virus-encoded EBNA1. Science 301, 1371–1374 (2003).

    Article  CAS  Google Scholar 

  47. Voo, K. S. et al. Evidence for the presentation of major histocompatibility complex class I-restricted Epstein–Barr virus nuclear antigen 1 peptides to CD8+ T lymphocytes. J. Exp. Med. 199, 459–470 (2004).

    Article  CAS  Google Scholar 

  48. Tellam, J. et al. Endogenous presentation of CD8+ T cell epitopes from Epstein–Barr virus-encoded nuclear antigen 1. J. Exp. Med. 199, 1421–1431 (2004).

    Article  CAS  Google Scholar 

  49. Lee, S. P. et al. CD8 T cell recognition of endogenously expressed Epstein–Barr virus nuclear antigen 1. J. Exp. Med. 199, 1409–1420 (2004).

    Article  CAS  Google Scholar 

  50. Rowe, M. et al. Restoration of endogenous antigen processing in Burkitt's lymphoma cells by Epstein–Barr virus latent membrane protein-1: coordinate upregulation of peptide transporters and HLA-class I antigen expression. Eur. J. Immunol. 25, 1374–1384 (1995).

    Article  CAS  Google Scholar 

  51. Paludan, C. et al. Epstein–Barr nuclear antigen 1-specific CD4+ TH1 cells kill Burkitt's lymphoma cells. J. Immunol. 169, 1593–1603 (2002).

    Article  CAS  Google Scholar 

  52. Bickham, K. et al. EBNA1-specific CD4+ T cells in healthy carriers of Epstein–Barr virus are primarily TH1 in function. J. Clin. Invest. 107, 121–130 (2001).

    Article  CAS  Google Scholar 

  53. Nikiforow, S., Bottomly, K., Miller, G. & Munz, C. Cytolytic CD4+-T-cell clones reactive to EBNA1 inhibit Epstein–Barr virus-induced B-cell proliferation. J. Virol. 77, 12088–12104 (2003).

    Article  CAS  Google Scholar 

  54. Khanna, R. et al. Targeting Epstein–Barr virus nuclear antigen 1 (EBNA1) through the class II pathway restores immune recognition by EBNA1-specific cytotoxic T lymphocytes: evidence for HLA-DM-independent processing. Int. Immunol. 9, 1537–1543 (1997).

    Article  CAS  Google Scholar 

  55. Wang, R. F. The role of MHC class II-restricted tumor antigens and CD4+ T cells in antitumor immunity. Trends Immunol. 22, 269–276 (2001).

    Article  Google Scholar 

  56. Fu, T., Voo, K. S. & Wang, R. F. Critical role of EBNA1-specific CD4+ T cells in the control of mouse Burkitt lymphoma in vivo. J. Clin. Invest. 114, 542–550 (2004).

    Article  CAS  Google Scholar 

  57. Urban, B. C. et al. Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic cells. Nature 400, 73–77 (1999).

    Article  CAS  Google Scholar 

  58. Urban, B. C., Willcox, N. & Roberts, D. J. A role for CD36 in the regulation of dendritic cell function. Proc. Natl Acad. Sci. USA 98, 8750–8755 (2001).

    Article  CAS  Google Scholar 

  59. Ocana-Morgner, C., Mota, M. M. & Rodriguez, A. Malaria blood stage suppression of liver stage immunity by dendritic cells. J. Exp. Med. 197, 143–151 (2003).

    Article  CAS  Google Scholar 

  60. Urban, B. C. et al. Peripheral blood dendritic cells in children with acute Plasmodium falciparum malaria. Blood 98, 2859–2861 (2001).

    Article  CAS  Google Scholar 

  61. Mills, K. H. & McGuirk, P. Antigen-specific regulatory T cells — their induction and role in infection. Semin. Immunol. 16, 107–117 (2004).

    Article  CAS  Google Scholar 

  62. Hugosson, E., Montgomery, S. M., Premji, Z., Troye-Blomberg, M. & Bjorkman, A. Higher IL-10 levels are associated with less effective clearance of Plasmodium falciparum parasites. Parasite Immunol. 26, 111–117 (2004).

    Article  CAS  Google Scholar 

  63. Gosi, P. et al. Complicated malaria is associated with differential elevations in serum levels of interleukins 10, 12, and 15. Southeast Asian J. Trop. Med. Public Health 30, 412–417 (1999).

    CAS  PubMed  Google Scholar 

  64. Paludan, C. & Munz, C. CD4+ T cell responses in the immune control against latent infection by Epstein–Barr virus. Curr. Mol. Med. 3, 341–347 (2003).

    Article  CAS  Google Scholar 

  65. Reece, W. H. et al. Naturally exposed populations differ in their T1 and T2 responses to the circumsporozoite protein of Plasmodium falciparum. Infect. Immun. 70, 1468–1474 (2002).

    Article  CAS  Google Scholar 

  66. Taylor-Robinson, A. W. & Smith, E. C. A role for cytokines in potentiation of malaria vaccines through immunological modulation of blood stage infection. Immunol. Rev. 171, 105–123 (1999).

    Article  CAS  Google Scholar 

  67. Snow, R. W. & Marsh, K. The consequences of reducing transmission of Plasmodium falciparum in Africa. Adv. Parasitol. 52, 235–264 (2002).

    Article  Google Scholar 

  68. Araujo, I. et al. Expression of Epstein–Barr virus gene products in Burkitt's lymphoma in Northeast Brazil. Blood 87, 5279–5286 (1996).

    CAS  PubMed  Google Scholar 

  69. Bacchi, M. M. et al. Burkitt's lymphoma in Brazil: strong association with Epstein–Barr virus. Mod. Pathol. 9, 63–67 (1996).

    CAS  PubMed  Google Scholar 

  70. Levine, A. M. Lymphoma complicating immunodeficiency disorders. Ann. Oncol. 5 (Suppl.), S29–S35 (1994).

    Article  Google Scholar 

  71. Shirai, A., Cosentino, M., Leitman-Klinman, S. F. & Klinman, D. M. Human immunodeficiency virus infection induces both polyclonal and virus-specific B cell activation. J. Clin. Invest. 89, 561–566 (1992).

    Article  CAS  Google Scholar 

  72. de-The, G. The Epstein–Barr virus (EBV): a Rosetta Stone for understanding the role of viruses in immunopathological disorders and in human carcinogenesis. Biomed. Pharmacother. 39, 49–51 (1985).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank the field assistants and the families for their participation in our studies.

Author information

Authors and Affiliations

  1. the Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York, USA

    Rosemary Rochford

  2. the Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansa, USA

    Martin J. Cannon

  3. the Center for Global Health and Diseases, Case Western Reserve University, Cleveland, Ohio, USA

    Ann M. Moormann

Authors
  1. Rosemary Rochford
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  2. Martin J. Cannon
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  3. Ann M. Moormann
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Correspondence to Rosemary Rochford.

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DATABASES

Infectious Disease Information

Epstein–Barr virus

malaria

FURTHER INFORMATION

Rosemary Rochford's laboratory

Glossary

ERYTHROCYTIC SCHIZOGONY

Asexual reproduction of malaria parasites in red blood cells.

HOLOENDEMIC MALARIA

Malaria that can be transmitted throughout the year and is common from year to year with little seasonal variation (perennial transmission). In regions where malaria is holoendemic, the number of children that have parasites in their blood can exceed 50% of the population.

MITOGEN

A substance that induces mitosis.

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Rochford, R., Cannon, M. & Moormann, A. Endemic Burkitt's lymphoma: a polymicrobial disease?. Nat Rev Microbiol 3, 182–187 (2005). https://doi.org/10.1038/nrmicro1089

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