Skip to main content
PMC home page
Infection and Immunity logoLink to Infection and Immunity
. 1997 Feb;65(2):373–379. doi: 10.1128/iai.65.2.373-379.1997

Role of gamma interferon in the host immune and inflammatory responses to Pneumocystis carinii infection.

B A Garvy 1, R A Ezekowitz 1, A G Harmsen 1
PMCID: PMC174605  PMID: 9009285

Abstract

The role of gamma interferon (IFN-gamma) in host defense to Pneumocystis carinii was investigated by use of three different murine models of infection. C57BL/6 scid/scid (severe combined immunodeficient [SCID]) mice were given intratracheal inoculations of P. carinii and reconstituted with splenocytes from either mice with disrupted IFN-gamma genes (IFN-gamma-/- mice) or homozygous wild-type (IFN-gamma+/+) mice. Unreconstituted SCID mice had log10 7.08 +/- 0.13 P. carinii nuclei in their lungs at day 22 postinfection, whereas SCID mice reconstituted with splenocytes from either wild-type or IFN-gamma-/- mice had cleared the infection. However, there was a prolonged and exacerbated inflammatory response in the lungs of SCID mice reconstituted with IFN-gamma-/- splenocytes which was characterized by interstitial pneumonia, eosinophilia, and multinucleated giant cell formation. Similar results were found in C.B17 SCID mice reconstituted with CD4+ cells from P. carinii-immunized donors treated with neutralizing anti-IFN-gamma monoclonal antibody (MAb). These mice resolved their P. carinii infections; however, they also exhibited exacerbated lung pathology compared with mice treated with a control MAb. Finally, IFN-gamma-/- mice challenged intratracheally with P. carinii resolved their infection within 56 days as did IFN-gamma+/- mice. Furthermore, depletion of T cells in vivo with a MAb resulted in IFN-gamma-/- mice becoming susceptible to P. carinii infection. Together, these data indicate that IFN-gamma is not required for resolution of P. carinii infection; however, in the absence of IFN-gamma, there is a prolonged and exacerbated P. carinii-driven interstitial pneumonia characterized by eosinophilia and formation of multinucleated giant cells.

Full Text

The Full Text of this article is available as a PDF (796.7 KB).

Selected References

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

  1. Beck J. M., Liggitt H. D., Brunette E. N., Fuchs H. J., Shellito J. E., Debs R. J. Reduction in intensity of Pneumocystis carinii pneumonia in mice by aerosol administration of gamma interferon. Infect Immun. 1991 Nov;59(11):3859–3862. doi: 10.1128/iai.59.11.3859-3862.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chen W., Havell E. A., Harmsen A. G. Importance of endogenous tumor necrosis factor alpha and gamma interferon in host resistance against Pneumocystis carinii infection. Infect Immun. 1992 Apr;60(4):1279–1284. doi: 10.1128/iai.60.4.1279-1284.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chen W., Mills J. W., Harmsen A. G. Development and resolution of Pneumocystis carinii pneumonia in severe combined immunodeficient mice: a morphological study of host inflammatory responses. Int J Exp Pathol. 1992 Dec;73(6):709–720. [PMC free article] [PubMed] [Google Scholar]
  4. Corry D. B., Folkesson H. G., Warnock M. L., Erle D. J., Matthay M. A., Wiener-Kronish J. P., Locksley R. M. Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J Exp Med. 1996 Jan 1;183(1):109–117. doi: 10.1084/jem.183.1.109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Coyle A. J., Tsuyuki S., Bertrand C., Huang S., Aguet M., Alkan S. S., Anderson G. P. Mice lacking the IFN-gamma receptor have impaired ability to resolve a lung eosinophilic inflammatory response associated with a prolonged capacity of T cells to exhibit a Th2 cytokine profile. J Immunol. 1996 Apr 15;156(8):2680–2685. [PubMed] [Google Scholar]
  6. Cushion M. T., Ruffolo J. J., Walzer P. D. Analysis of the developmental stages of Pneumocystis carinii, in vitro. Lab Invest. 1988 Mar;58(3):324–331. [PubMed] [Google Scholar]
  7. Dunn P. L., North R. J. The importance of route of infection in determining the extent of exacerbation of listeriosis by anti-interferon-gamma monoclonal antibody. J Interferon Res. 1991 Oct;11(5):291–295. doi: 10.1089/jir.1991.11.291. [DOI] [PubMed] [Google Scholar]
  8. Harmsen A. G., Chen W., Gigliotti F. Active immunity to Pneumocystis carinii reinfection in T-cell-depleted mice. Infect Immun. 1995 Jul;63(7):2391–2395. doi: 10.1128/iai.63.7.2391-2395.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Harmsen A. G. Role of alveolar macrophages in lipopolysaccharide-induced neutrophil accumulation. Infect Immun. 1988 Aug;56(8):1858–1863. doi: 10.1128/iai.56.8.1858-1863.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Harmsen A. G., Stankiewicz M. Requirement for CD4+ cells in resistance to Pneumocystis carinii pneumonia in mice. J Exp Med. 1990 Sep 1;172(3):937–945. doi: 10.1084/jem.172.3.937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Havell E. A. Purification and further characterization of an anti-murine interferon-gamma monoclonal neutralizing antibody. J Interferon Res. 1986 Oct;6(5):489–497. doi: 10.1089/jir.1986.6.489. [DOI] [PubMed] [Google Scholar]
  12. Ishimine T., Kawakami K., Nakamoto A., Saito A. Analysis of cellular response and gamma interferon synthesis in bronchoalveolar lavage fluid and lung homogenate of mice infected with Pneumocystis carinii. Microbiol Immunol. 1995;39(1):49–58. doi: 10.1111/j.1348-0421.1995.tb02167.x. [DOI] [PubMed] [Google Scholar]
  13. Lee W. T., Yin X. M., Vitetta E. S. Functional and ontogenetic analysis of murine CD45Rhi and CD45Rlo CD4+ T cells. J Immunol. 1990 May 1;144(9):3288–3295. [PubMed] [Google Scholar]
  14. Mosmann T. R., Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996 Mar;17(3):138–146. doi: 10.1016/0167-5699(96)80606-2. [DOI] [PubMed] [Google Scholar]
  15. Pesanti E. L. Interaction of cytokines and alveolar cells with Pneumocystis carinii in vitro. J Infect Dis. 1991 Mar;163(3):611–616. doi: 10.1093/infdis/163.3.611. [DOI] [PubMed] [Google Scholar]
  16. Roths J. B., Sidman C. L. Both immunity and hyperresponsiveness to Pneumocystis carinii result from transfer of CD4+ but not CD8+ T cells into severe combined immunodeficiency mice. J Clin Invest. 1992 Aug;90(2):673–678. doi: 10.1172/JCI115910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Shear H. L., Valladares G., Narachi M. A. Enhanced treatment of Pneumocystis carinii pneumonia in rats with interferon-gamma and reduced doses of trimethoprim/sulfamethoxazole. J Acquir Immune Defic Syndr. 1990;3(10):943–948. [PubMed] [Google Scholar]
  18. Suzuki Y., Orellana M. A., Schreiber R. D., Remington J. S. Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science. 1988 Apr 22;240(4851):516–518. doi: 10.1126/science.3128869. [DOI] [PubMed] [Google Scholar]
  19. Swain S. L. Generation and in vivo persistence of polarized Th1 and Th2 memory cells. Immunity. 1994 Oct;1(7):543–552. doi: 10.1016/1074-7613(94)90044-2. [DOI] [PubMed] [Google Scholar]
  20. Wiley J. A., Harmsen A. G. CD40 ligand is required for resolution of Pneumocystis carinii pneumonia in mice. J Immunol. 1995 Oct 1;155(7):3525–3529. [PubMed] [Google Scholar]
  21. Williams D. M., Byrne G. I., Grubbs B., Marshal T. J., Schachter J. Role in vivo for gamma interferon in control of pneumonia caused by Chlamydia trachomatis in mice. Infect Immun. 1988 Nov;56(11):3004–3006. doi: 10.1128/iai.56.11.3004-3006.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Wilson R. A., Coulson P. S., Betts C., Dowling M. A., Smythies L. E. Impaired immunity and altered pulmonary responses in mice with a disrupted interferon-gamma receptor gene exposed to the irradiated Schistosoma mansoni vaccine. Immunology. 1996 Feb;87(2):275–282. doi: 10.1046/j.1365-2567.1996.465550.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES