Skip to main content
PMC home page
Infection and Immunity logoLink to Infection and Immunity
. 1995 Sep;63(9):3514–3519. doi: 10.1128/iai.63.9.3514-3519.1995

Roles of gamma interferon and interleukin-4 in genetically determined resistance to Coccidioides immitis.

D M Magee 1, R A Cox 1
PMCID: PMC173486  PMID: 7642285

Abstract

The profiles of gamma interferon (IFN-gamma) and interleukin-4 (IL-4) production were evaluated during the course of coccidioidomycosis in two inbred mouse strains which differ in their susceptibility to Coccidioides immitis. Cytokine responses, measured at the molecular and protein levels, showed increased levels of IFN-gamma in lung extracts from mice of the resistant DBA/2 strain after a pulmonary challenge, whereas the susceptible BALB/c strain manifested a predominant IL-4 response. The importance of these cytokines in host defense against C. immitis was established by treating the mice with recombinant cytokines or neutralizing anticytokine monoclonal antibodies. Treatment of the susceptible BALB/c mice with recombinant murine IFN-gamma significantly protected mice against systemic challenge, and in the reciprocal experiment, the administration of an anti-IFN-gamma monoclonal antibody to the resistant DBA/2 mice significantly decreased their capacity to control disease. Although the treatment of DBA/2 mice with recombinant IL-4 did not alter the disease, neutralization of endogenous IL-4 in infected BALB/c mice by administration of a neutralizing anti-IL-4 antibody led to a significant reduction in the fungal load in their tissues. These results, taken together, establish that IFN-gamma plays a pivotal role in resistance to C. immitis, whereas IL-4 down-regulates protective immunity against C. immitis.

Full Text

The Full Text of this article is available as a PDF (297.1 KB).

Selected References

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

  1. Ampel N. M., Bejarano G. C., Salas S. D., Galgiani J. N. In vitro assessment of cellular immunity in human coccidioidomycosis: relationship between dermal hypersensitivity, lymphocyte transformation, and lymphokine production by peripheral blood mononuclear cells from healthy adults. J Infect Dis. 1992 Apr;165(4):710–715. doi: 10.1093/infdis/165.4.710. [DOI] [PubMed] [Google Scholar]
  2. Ampel N. M. In vitro production of tumor necrosis factor-alpha by adherent human peripheral blood mononuclear cells incubated with killed coccidioidal arthroconidia and spherules. Cell Immunol. 1994 Jan;153(1):248–255. doi: 10.1006/cimm.1994.1022. [DOI] [PubMed] [Google Scholar]
  3. Ampel N. M., Wieden M. A., Galgiani J. N. Coccidioidomycosis: clinical update. Rev Infect Dis. 1989 Nov-Dec;11(6):897–911. doi: 10.1093/clinids/11.6.897. [DOI] [PubMed] [Google Scholar]
  4. Beaman L. Effects of recombinant gamma interferon and tumor necrosis factor on in vitro interactions of human mononuclear phagocytes with Coccidioides immitis. Infect Immun. 1991 Nov;59(11):4227–4229. doi: 10.1128/iai.59.11.4227-4229.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Beaman L. Fungicidal activation of murine macrophages by recombinant gamma interferon. Infect Immun. 1987 Dec;55(12):2951–2955. doi: 10.1128/iai.55.12.2951-2955.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bohn E., Heesemann J., Ehlers S., Autenrieth I. B. Early gamma interferon mRNA expression is associated with resistance of mice against Yersinia enterocolitica. Infect Immun. 1994 Jul;62(7):3027–3032. doi: 10.1128/iai.62.7.3027-3032.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cox R. A., Arnold D. R. Immunoglobulin E in coccidioidomycosis. J Immunol. 1979 Jul;123(1):194–200. [PubMed] [Google Scholar]
  8. Cox R. A., Kennell W., Boncyk L., Murphy J. W. Induction and expression of cell-mediated immune responses in inbred mice infected with Coccidioides immitis. Infect Immun. 1988 Jan;56(1):13–17. doi: 10.1128/iai.56.1.13-17.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cox R. A., Kennell W. Suppression of T-lymphocyte response by Coccidioides immitis antigen. Infect Immun. 1988 Jun;56(6):1424–1429. doi: 10.1128/iai.56.6.1424-1429.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cox R. A., Vivas J. R. Spectrum of in vivo and in vitro cell-mediated immune responses in coccidioidomycosis. Cell Immunol. 1977 Jun 1;31(1):130–141. doi: 10.1016/0008-8749(77)90012-0. [DOI] [PubMed] [Google Scholar]
  11. Dooley D. P., Cox R. A., Hestilow K. L., Dolan M. J., Magee D. M. Cytokine induction in human coccidioidomycosis. Infect Immun. 1994 Sep;62(9):3980–3983. doi: 10.1128/iai.62.9.3980-3983.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Drutz D. J., Catanzaro A. Coccidioidomycosis. Part I. Am Rev Respir Dis. 1978 Mar;117(3):559–585. doi: 10.1164/arrd.1978.117.3.559. [DOI] [PubMed] [Google Scholar]
  13. Drutz D. J., Catanzaro A. Coccidioidomycosis. Part II. Am Rev Respir Dis. 1978 Apr;117(4):727–771. doi: 10.1164/arrd.1978.117.4.727. [DOI] [PubMed] [Google Scholar]
  14. Gray P. W., Goeddel D. V. Cloning and expression of murine immune interferon cDNA. Proc Natl Acad Sci U S A. 1983 Oct;80(19):5842–5846. doi: 10.1073/pnas.80.19.5842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Heinzel F. P., Sadick M. D., Holaday B. J., Coffman R. L., Locksley R. M. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med. 1989 Jan 1;169(1):59–72. doi: 10.1084/jem.169.1.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Heinzel F. P., Sadick M. D., Mutha S. S., Locksley R. M. Production of interferon gamma, interleukin 2, interleukin 4, and interleukin 10 by CD4+ lymphocytes in vivo during healing and progressive murine leishmaniasis. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7011–7015. doi: 10.1073/pnas.88.16.7011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hoft D. F., Lynch R. G., Kirchhoff L. V. Kinetic analysis of antigen-specific immune responses in resistant and susceptible mice during infection with Trypanosoma cruzi. J Immunol. 1993 Dec 15;151(12):7038–7047. [PubMed] [Google Scholar]
  18. Iizawa Y., Wagner R. D., Czuprynski C. J. Analysis of cytokine mRNA expression in Listeria-resistant C57BL/6 and Listeria-susceptible A/J mice during Listeria monocytogenes infection. Infect Immun. 1993 Sep;61(9):3739–3744. doi: 10.1128/iai.61.9.3739-3744.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jaffe H. A., Buhl R., Mastrangeli A., Holroyd K. J., Saltini C., Czerski D., Jaffe H. S., Kramer S., Sherwin S., Crystal R. G. Organ specific cytokine therapy. Local activation of mononuclear phagocytes by delivery of an aerosol of recombinant interferon-gamma to the human lung. J Clin Invest. 1991 Jul;88(1):297–302. doi: 10.1172/JCI115291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kirkland T. N., Fierer J. Inbred mouse strains differ in resistance to lethal Coccidioides immitis infection. Infect Immun. 1983 Jun;40(3):912–916. doi: 10.1128/iai.40.3.912-916.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Montgomery R. A., Dallman M. J. Analysis of cytokine gene expression during fetal thymic ontogeny using the polymerase chain reaction. J Immunol. 1991 Jul 15;147(2):554–560. [PubMed] [Google Scholar]
  22. Morris L., Troutt A. B., McLeod K. S., Kelso A., Handman E., Aebischer T. Interleukin-4 but not gamma interferon production correlates with the severity of murine cutaneous leishmaniasis. Infect Immun. 1993 Aug;61(8):3459–3465. doi: 10.1128/iai.61.8.3459-3465.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. Murphy E., Hieny S., Sher A., O'Garra A. Detection of in vivo expression of interleukin-10 using a semi-quantitative polymerase chain reaction method in Schistosoma mansoni infected mice. J Immunol Methods. 1993 Jun 18;162(2):211–223. doi: 10.1016/0022-1759(93)90386-l. [DOI] [PubMed] [Google Scholar]
  25. Noma Y., Sideras P., Naito T., Bergstedt-Lindquist S., Azuma C., Severinson E., Tanabe T., Kinashi T., Matsuda F., Yaoita Y. Cloning of cDNA encoding the murine IgG1 induction factor by a novel strategy using SP6 promoter. Nature. 1986 Feb 20;319(6055):640–646. doi: 10.1038/319640a0. [DOI] [PubMed] [Google Scholar]
  26. O'Garra A., Vieira P. Polymerase chain reaction for detection of cytokine gene expression. Curr Opin Immunol. 1992 Apr;4(2):211–215. doi: 10.1016/0952-7915(92)90016-8. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Orme I. M., Roberts A. D., Griffin J. P., Abrams J. S. Cytokine secretion by CD4 T lymphocytes acquired in response to Mycobacterium tuberculosis infection. J Immunol. 1993 Jul 1;151(1):518–525. [PubMed] [Google Scholar]
  29. Pappagianis D. Epidemiology of coccidioidomycosis. Curr Top Med Mycol. 1988;2:199–238. doi: 10.1007/978-1-4612-3730-3_6. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Romani L., Mocci S., Bietta C., Lanfaloni L., Puccetti P., Bistoni F. Th1 and Th2 cytokine secretion patterns in murine candidiasis: association of Th1 responses with acquired resistance. Infect Immun. 1991 Dec;59(12):4647–4654. doi: 10.1128/iai.59.12.4647-4654.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sadick M. D., Heinzel F. P., Holaday B. J., Pu R. T., Dawkins R. S., Locksley R. M. Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism. J Exp Med. 1990 Jan 1;171(1):115–127. doi: 10.1084/jem.171.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Scharton T. M., Scott P. Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. J Exp Med. 1993 Aug 1;178(2):567–577. doi: 10.1084/jem.178.2.567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sher A., Coffman R. L. Regulation of immunity to parasites by T cells and T cell-derived cytokines. Annu Rev Immunol. 1992;10:385–409. doi: 10.1146/annurev.iy.10.040192.002125. [DOI] [PubMed] [Google Scholar]
  35. Sher A., Gazzinelli R. T., Oswald I. P., Clerici M., Kullberg M., Pearce E. J., Berzofsky J. A., Mosmann T. R., James S. L., Morse H. C., 3rd Role of T-cell derived cytokines in the downregulation of immune responses in parasitic and retroviral infection. Immunol Rev. 1992 Jun;127:183–204. doi: 10.1111/j.1600-065x.1992.tb01414.x. [DOI] [PubMed] [Google Scholar]
  36. Treuhaft M. W., Beem M. O. Defective interfering particles of respiratory syncytial virus. Infect Immun. 1982 Aug;37(2):439–444. doi: 10.1128/iai.37.2.439-444.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Wesselingh S. L., Levine B., Fox R. J., Choi S., Griffin D. E. Intracerebral cytokine mRNA expression during fatal and nonfatal alphavirus encephalitis suggests a predominant type 2 T cell response. J Immunol. 1994 Feb 1;152(3):1289–1297. [PubMed] [Google Scholar]
  38. Xu Y. H., Macedonia J., Sher A., Pearce E., Cheever A. W. Dynamic analysis of splenic Th1 and Th2 lymphocyte functions in mice infected with Schistosoma japonicum. Infect Immun. 1991 Sep;59(9):2934–2940. doi: 10.1128/iai.59.9.2934-2940.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES