Skip to main content
Infection and Immunity logoLink to Infection and Immunity
. 1995 Oct;63(10):3987–3993. doi: 10.1128/iai.63.10.3987-3993.1995

Cellular mechanisms in the immune response to malaria in Plasmodium vinckei-infected mice.

H Perlmann 1, S Kumar 1, J M Vinetz 1, M Kullberg 1, L H Miller 1, P Perlmann 1
PMCID: PMC173560  PMID: 7558309

Abstract

Infection of mice with the malaria parasite Plasmodium vinckei vinckei is 100% lethal. However, after two infections followed by drug cure, BALB/c mice develop a solid immunity which is antibody independent but mediated by CD4+ T cells. To elucidate the mechanisms of this immunity, spleen cells from immune mice were challenged in vitro with lysates of P. vinckei-infected or uninfected erythrocytes. The parasite antigen induced proliferation of T cells from immune mice but not from nonimmune mice. When gamma interferon production by cells from immune mice was assayed at the single-cell level, 1 to 3 cells per 1,000 cells were found to release this cytokine when exposed to antigen. In contrast, the numbers of interleukin 4 (IL-4)-producing cells from both immune and control mice were < or = 4 per 10(6) cells, regardless of antigen exposure. Investigation in a bioassay showed that P. vinckei antigen induced the release of IL-4 from spleen cells of immune mice but not from those of control mice. Nevertheless, that IL-4 is of minor significance in this system is also suggested by the absence of elevation of immunoglobulin E levels in blood samples from these mice, in contrast to what is seen with P. chabaudi infection, in which IL-4-producing Th2 cells are of major importance for immunity during later phases of infection. Taken together, the present results indicate that immunity to P. vinckei is a Th1 response, with gamma interferon being an important protective factor. Whether or not the Th1 response, through overproduction of tumor necrosis factor alpha, is also responsible for pathology and death in this infection remains to be clarified.

Full Text

The Full Text of this article is available as a PDF (762.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bate C. A., Taverne J., Bootsma H. J., Mason R. C., Skalko N., Gregoriadis G., Playfair J. H. Antibodies against phosphatidylinositol and inositol monophosphate specifically inhibit tumour necrosis factor induction by malaria exoantigens. Immunology. 1992 May;76(1):35–41. [PMC free article] [PubMed] [Google Scholar]
  2. Bienzle U., Fritsch K. G., Hoth G., Rozdzinski E., Köhler K., Kalinowski M., Kremsner P., Rosenkaimer F., Feldmeier H. Inhibition of Plasmodium vinckei-malaria in mice by recombinant murine interferon-gamma. Acta Trop. 1988 Sep;45(3):289–290. [PubMed] [Google Scholar]
  3. Boros D. L., Warren K. S. Delayed hypersensitivity-type granuloma formation and dermal reaction induced and elicited by a soluble factor isolated from Schistosoma mansoni eggs. J Exp Med. 1970 Sep 1;132(3):488–507. doi: 10.1084/jem.132.3.488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cherwinski H. M., Schumacher J. H., Brown K. D., Mosmann T. R. Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med. 1987 Nov 1;166(5):1229–1244. doi: 10.1084/jem.166.5.1229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Clark I. A., Chaudhri G. Tumour necrosis factor may contribute to the anaemia of malaria by causing dyserythropoiesis and erythrophagocytosis. Br J Haematol. 1988 Sep;70(1):99–103. doi: 10.1111/j.1365-2141.1988.tb02440.x. [DOI] [PubMed] [Google Scholar]
  6. Clark I. A., Hunt N. H., Butcher G. A., Cowden W. B. Inhibition of murine malaria (Plasmodium chabaudi) in vivo by recombinant interferon-gamma or tumor necrosis factor, and its enhancement by butylated hydroxyanisole. J Immunol. 1987 Nov 15;139(10):3493–3496. [PubMed] [Google Scholar]
  7. Clark I. A., MacMicking J. D., Gray K. M., Rockett K. A., Cowden W. B. Malaria mimicry with tumor necrosis factor. Contrasts between species of murine malaria and Plasmodium falciparum. Am J Pathol. 1992 Feb;140(2):325–336. [PMC free article] [PubMed] [Google Scholar]
  8. Collart M. A., Belin D., Vassalli J. D., de Kossodo S., Vassalli P. Gamma interferon enhances macrophage transcription of the tumor necrosis factor/cachectin, interleukin 1, and urokinase genes, which are controlled by short-lived repressors. J Exp Med. 1986 Dec 1;164(6):2113–2118. doi: 10.1084/jem.164.6.2113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Curry R. C., Kiener P. A., Spitalny G. L. A sensitive immunochemical assay for biologically active MuIFN-gamma. J Immunol Methods. 1987 Nov 23;104(1-2):137–142. doi: 10.1016/0022-1759(87)90497-2. [DOI] [PubMed] [Google Scholar]
  10. Czerkinsky C., Andersson G., Ekre H. P., Nilsson L. A., Klareskog L., Ouchterlony O. Reverse ELISPOT assay for clonal analysis of cytokine production. I. Enumeration of gamma-interferon-secreting cells. J Immunol Methods. 1988 May 25;110(1):29–36. doi: 10.1016/0022-1759(88)90079-8. [DOI] [PubMed] [Google Scholar]
  11. Ferreira A., Schofield L., Enea V., Schellekens H., van der Meide P., Collins W. E., Nussenzweig R. S., Nussenzweig V. Inhibition of development of exoerythrocytic forms of malaria parasites by gamma-interferon. Science. 1986 May 16;232(4752):881–884. doi: 10.1126/science.3085218. [DOI] [PubMed] [Google Scholar]
  12. Finnemann S., Kremsner P. G., Chaves M. F., Schumacher C., Neifer S., Bienzle U. Antibody response in Plasmodium vinckei malaria after treatment with chloroquine and adjuvant interferon-gamma. Parasitol Res. 1992;78(8):629–634. doi: 10.1007/BF00931511. [DOI] [PubMed] [Google Scholar]
  13. Grau G. E., Fajardo L. F., Piguet P. F., Allet B., Lambert P. H., Vassalli P. Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science. 1987 Sep 4;237(4819):1210–1212. doi: 10.1126/science.3306918. [DOI] [PubMed] [Google Scholar]
  14. Grau G. E., Heremans H., Piguet P. F., Pointaire P., Lambert P. H., Billiau A., Vassalli P. Monoclonal antibody against interferon gamma can prevent experimental cerebral malaria and its associated overproduction of tumor necrosis factor. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5572–5574. doi: 10.1073/pnas.86.14.5572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Grun J. L., Weidanz W. P. Antibody-independent immunity to reinfection malaria in B-cell-deficient mice. Infect Immun. 1983 Sep;41(3):1197–1204. doi: 10.1128/iai.41.3.1197-1204.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Grzych J. M., Pearce E., Cheever A., Caulada Z. A., Caspar P., Heiny S., Lewis F., Sher A. Egg deposition is the major stimulus for the production of Th2 cytokines in murine schistosomiasis mansoni. J Immunol. 1991 Feb 15;146(4):1322–1327. [PubMed] [Google Scholar]
  17. Hu-Li J., Ohara J., Watson C., Tsang W., Paul W. E. Derivation of a T cell line that is highly responsive to IL-4 and IL-2 (CT.4R) and of an IL-2 hyporesponsive mutant of that line (CT.4S). J Immunol. 1989 Feb 1;142(3):800–807. [PubMed] [Google Scholar]
  18. Kremsner P. G., Neifer S., Chaves M. F., Rudolph R., Bienzle U. Interferon-gamma induced lethality in the late phase of Plasmodium vinckei malaria despite effective parasite clearance by chloroquine. Eur J Immunol. 1992 Nov;22(11):2873–2878. doi: 10.1002/eji.1830221118. [DOI] [PubMed] [Google Scholar]
  19. Kullberg M. C., Pearce E. J., Hieny S. E., Sher A., Berzofsky J. A. Infection with Schistosoma mansoni alters Th1/Th2 cytokine responses to a non-parasite antigen. J Immunol. 1992 May 15;148(10):3264–3270. [PubMed] [Google Scholar]
  20. Kumar S., Good M. F., Dontfraid F., Vinetz J. M., Miller L. H. Interdependence of CD4+ T cells and malarial spleen in immunity to Plasmodium vinckei vinckei. Relevance to vaccine development. J Immunol. 1989 Sep 15;143(6):2017–2023. [PubMed] [Google Scholar]
  21. Langhorne J., Gillard S., Simon B., Slade S., Eichmann K. Frequencies of CD4+ T cells reactive with Plasmodium chabaudi chabaudi: distinct response kinetics for cells with Th1 and Th2 characteristics during infection. Int Immunol. 1989;1(4):416–424. doi: 10.1093/intimm/1.4.416. [DOI] [PubMed] [Google Scholar]
  22. Langhorne J., Meding S. J., Eichmann K., Gillard S. S. The response of CD4+ T cells to Plasmodium chabaudi chabaudi. Immunol Rev. 1989 Dec;112:71–94. doi: 10.1111/j.1600-065x.1989.tb00553.x. [DOI] [PubMed] [Google Scholar]
  23. Maheshwari R. K., Czarniecki C. W., Dutta G. P., Puri S. K., Dhawan B. N., Friedman R. M. Recombinant human gamma interferon inhibits simian malaria. Infect Immun. 1986 Sep;53(3):628–630. doi: 10.1128/iai.53.3.628-630.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Meding S. J., Langhorne J. CD4+ T cells and B cells are necessary for the transfer of protective immunity to Plasmodium chabaudi chabaudi. Eur J Immunol. 1991 Jun;21(6):1433–1438. doi: 10.1002/eji.1830210616. [DOI] [PubMed] [Google Scholar]
  25. Mosmann T. R., Coffman R. L. Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol. 1989;46:111–147. doi: 10.1016/s0065-2776(08)60652-5. [DOI] [PubMed] [Google Scholar]
  26. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  27. Mosmann T. R., Schumacher J. H., Street N. F., Budd R., O'Garra A., Fong T. A., Bond M. W., Moore K. W., Sher A., Fiorentino D. F. Diversity of cytokine synthesis and function of mouse CD4+ T cells. Immunol Rev. 1991 Oct;123:209–229. doi: 10.1111/j.1600-065x.1991.tb00612.x. [DOI] [PubMed] [Google Scholar]
  28. Ohara J., Paul W. E. Production of a monoclonal antibody to and molecular characterization of B-cell stimulatory factor-1. Nature. 1985 May 23;315(6017):333–336. doi: 10.1038/315333a0. [DOI] [PubMed] [Google Scholar]
  29. Pearce E. J., Caspar P., Grzych J. M., Lewis F. A., Sher A. Downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma mansoni. J Exp Med. 1991 Jan 1;173(1):159–166. doi: 10.1084/jem.173.1.159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Perlmann H., Helmby H., Hagstedt M., Carlson J., Larsson P. H., Troye-Blomberg M., Perlmann P. IgE elevation and IgE anti-malarial antibodies in Plasmodium falciparum malaria: association of high IgE levels with cerebral malaria. Clin Exp Immunol. 1994 Aug;97(2):284–292. doi: 10.1111/j.1365-2249.1994.tb06082.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Phillips S. Effector mechanisms against asexual erythrocytic stages of Plasmodium. Immunol Lett. 1994 Jul;41(2-3):109–114. doi: 10.1016/0165-2478(94)90117-1. [DOI] [PubMed] [Google Scholar]
  32. Sayles P. C., Wassom D. L. Are antibodies important in mice infected with Plasmodium yoelii? Parasitol Today. 1992 Nov;8(11):368–370. doi: 10.1016/0169-4758(92)90172-x. [DOI] [PubMed] [Google Scholar]
  33. Schetters T. P., Van Run van Breda J. H., Hermsen C., Curfs J., Eling W. M. Protective and pathological activity in serum of mice developing resistance to Plasmodium berghei infection. Parasite Immunol. 1989 Jul;11(4):413–423. doi: 10.1111/j.1365-3024.1989.tb00678.x. [DOI] [PubMed] [Google Scholar]
  34. Schofield L., Hackett F. Signal transduction in host cells by a glycosylphosphatidylinositol toxin of malaria parasites. J Exp Med. 1993 Jan 1;177(1):145–153. doi: 10.1084/jem.177.1.145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Scott P. Selective differentiation of CD4+ T helper cell subsets. Curr Opin Immunol. 1993 Jun;5(3):391–397. doi: 10.1016/0952-7915(93)90058-z. [DOI] [PubMed] [Google Scholar]
  36. Shear H. L., Ng C., Zhao Y. Cytokine production in lethal and non-lethal murine malaria. Immunol Lett. 1990 Aug;25(1-3):123–127. doi: 10.1016/0165-2478(90)90102-v. [DOI] [PubMed] [Google Scholar]
  37. Shear H. L., Srinivasan R., Nolan T., Ng C. Role of IFN-gamma in lethal and nonlethal malaria in susceptible and resistant murine hosts. J Immunol. 1989 Sep 15;143(6):2038–2044. [PubMed] [Google Scholar]
  38. Stevenson M. M., Ghadirian E. Human recombinant tumor necrosis factor alpha protects susceptible A/J mice against lethal Plasmodium chabaudi AS infection. Infect Immun. 1989 Dec;57(12):3936–3939. doi: 10.1128/iai.57.12.3936-3939.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Stevenson M. M., Tam M. F., Belosevic M., van der Meide P. H., Podoba J. E. Role of endogenous gamma interferon in host response to infection with blood-stage Plasmodium chabaudi AS. Infect Immun. 1990 Oct;58(10):3225–3232. doi: 10.1128/iai.58.10.3225-3232.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Stevenson M. M., Tam M. F. Differential induction of helper T cell subsets during blood-stage Plasmodium chabaudi AS infection in resistant and susceptible mice. Clin Exp Immunol. 1993 Apr;92(1):77–83. doi: 10.1111/j.1365-2249.1993.tb05951.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Taylor-Robinson A. W., Phillips R. S. Functional characterization of protective CD4+ T-cell clones reactive to the murine malaria parasite Plasmodium chabaudi. Immunology. 1992 Sep;77(1):99–105. [PMC free article] [PubMed] [Google Scholar]
  42. Taylor-Robinson A. W., Phillips R. S. Th1 and Th2 CD4+ T cell clones specific for Plasmodium chabaudi but not for an unrelated antigen protect against blood stage P. chabaudi infection. Eur J Immunol. 1994 Jan;24(1):158–164. doi: 10.1002/eji.1830240124. [DOI] [PubMed] [Google Scholar]
  43. Trinchieri G. Interleukin-12 and its role in the generation of TH1 cells. Immunol Today. 1993 Jul;14(7):335–338. doi: 10.1016/0167-5699(93)90230-I. [DOI] [PubMed] [Google Scholar]
  44. Troye-Blomberg M., Berzins K., Perlmann P. T-cell control of immunity to the asexual blood stages of the malaria parasite. Crit Rev Immunol. 1994;14(2):131–155. doi: 10.1615/critrevimmunol.v14.i2.20. [DOI] [PubMed] [Google Scholar]
  45. Troye-Blomberg M., Riley E. M., Kabilan L., Holmberg M., Perlmann H., Andersson U., Heusser C. H., Perlmann P. Production by activated human T cells of interleukin 4 but not interferon-gamma is associated with elevated levels of serum antibodies to activating malaria antigens. Proc Natl Acad Sci U S A. 1990 Jul;87(14):5484–5488. doi: 10.1073/pnas.87.14.5484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Wasserman G. M., Kumar S., Ahlers J., Ramsdell F., Berzofsky J. A., Miller L. H. An approach to development of specific T-lymphocyte lines by use of preprocessed antigens in Plasmodium vinckei vinckei murine malaria. Infect Immun. 1993 May;61(5):1958–1963. doi: 10.1128/iai.61.5.1958-1963.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Weidanz W. P., Melancon-Kaplan J., Cavacini L. A. Cell-mediated immunity to the asexual blood stages of malarial parasites: animal models. Immunol Lett. 1990 Aug;25(1-3):87–95. doi: 10.1016/0165-2478(90)90097-a. [DOI] [PubMed] [Google Scholar]
  48. Weinbaum F. I., Evans C. B., Tigelaar R. E. Immunity to Plasmodium Berghei yoelii in mice. I. The course of infection in T cell and B cell deficient mice. J Immunol. 1976 Nov;117(5 PT2):1999–2005. [PubMed] [Google Scholar]
  49. White W. I., Evans C. B., Taylor D. W. Antimalarial antibodies of the immunoglobulin G2a isotype modulate parasitemias in mice infected with Plasmodium yoelii. Infect Immun. 1991 Oct;59(10):3547–3554. doi: 10.1128/iai.59.10.3547-3554.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Williams M. E., Kullberg M. C., Barbieri S., Caspar P., Berzofsky J. A., Seder R. A., Sher A. Fc epsilon receptor-positive cells are a major source of antigen-induced interleukin-4 in spleens of mice infected with Schistosoma mansoni. Eur J Immunol. 1993 Aug;23(8):1910–1916. doi: 10.1002/eji.1830230827. [DOI] [PubMed] [Google Scholar]
  51. de Vries J. E., Gauchat J. F., Aversa G. G., Punnonen J., Gascan H., Yssel H. Regulation of IgE synthesis by cytokines. Curr Opin Immunol. 1991 Dec;3(6):851–858. doi: 10.1016/s0952-7915(05)80003-2. [DOI] [PubMed] [Google Scholar]
  52. van der Heyde H. C., Manning D. D., Weidanz W. P. Role of CD4+ T cells in the expansion of the CD4-, CD8- gamma delta T cell subset in the spleens of mice during blood-stage malaria. J Immunol. 1993 Dec 1;151(11):6311–6317. [PubMed] [Google Scholar]
  53. von der Weid T., Kopf M., Köhler G., Langhorne J. The immune response to Plasmodium chabaudi malaria in interleukin-4-deficient mice. Eur J Immunol. 1994 Oct;24(10):2285–2293. doi: 10.1002/eji.1830241004. [DOI] [PubMed] [Google Scholar]
  54. von der Weid T., Langhorne J. The roles of cytokines produced in the immune response to the erythrocytic stages of mouse malarias. Immunobiology. 1993 Nov;189(3-4):397–418. doi: 10.1016/s0171-2985(11)80367-0. [DOI] [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES