Abstract
We examined the immunobiological responses to Histoplasma capsulatum in lungs of gamma interferon (IFN-gamma) knockout mice (GKO mice). Naive GKO mice succumbed by day 9 to intranasal challenge with 2.5 x 10(6) yeasts, whereas all wild-type (WT) mice survived for 45 days. Compared to lungs of WT mice, the lungs of acutely infected GKO mice exhibited dramatically elevated numbers of CFU in lungs and significantly higher levels of tumor necrosis factor alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF) but not interleukin-12 (IL-12) or IL-4. To determine if IFN-gamma is necessary in reexposure histoplasmosis, GKO and WT mice were inoculated with 10(4) yeasts intranasally and given amphotericin B for 3 weeks. Six weeks later, mice were rechallenged with 2.5 x 10(6) yeasts. All GKO mice died by day 6, whereas all WT mice survived for 45 days. Lungs of GKO mice contained substantially elevated numbers of CFU and higher TNF-alpha and GM-CSF levels but not IL-12 or IL-4. Thus, IFN-gamma is requisite for control of pulmonary histoplasmosis in naive and reexposed mice.
Full Text
The Full Text of this article is available as a PDF (515.0 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Allendoerfer R., Biovin G. P., Deepe G. S., Jr Modulation of immune responses in murine pulmonary histoplasmosis. J Infect Dis. 1997 Apr;175(4):905–914. doi: 10.1086/513989. [DOI] [PubMed] [Google Scholar]
- Allendoerfer R., Magee D. M., Deepe G. S., Jr, Graybill J. R. Transfer of protective immunity in murine histoplasmosis by a CD4+ T-cell clone. Infect Immun. 1993 Feb;61(2):714–718. doi: 10.1128/iai.61.2.714-718.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chia J. K., Pollack M. Amphotericin B induces tumor necrosis factor production by murine macrophages. J Infect Dis. 1989 Jan;159(1):113–116. doi: 10.1093/infdis/159.1.113. [DOI] [PubMed] [Google Scholar]
- Cooper A. M., Dalton D. K., Stewart T. A., Griffin J. P., Russell D. G., Orme I. M. Disseminated tuberculosis in interferon gamma gene-disrupted mice. J Exp Med. 1993 Dec 1;178(6):2243–2247. doi: 10.1084/jem.178.6.2243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Deepe G. S., Jr Role of CD8+ T cells in host resistance to systemic infection with Histoplasma capsulatum in mice. J Immunol. 1994 Apr 1;152(7):3491–3500. [PubMed] [Google Scholar]
- Dinarello C. A., Cannon J. G., Wolff S. M., Bernheim H. A., Beutler B., Cerami A., Figari I. S., Palladino M. A., Jr, O'Connor J. V. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med. 1986 Jun 1;163(6):1433–1450. doi: 10.1084/jem.163.6.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Flesch I. E., Hess J. H., Huang S., Aguet M., Rothe J., Bluethmann H., Kaufmann S. H. Early interleukin 12 production by macrophages in response to mycobacterial infection depends on interferon gamma and tumor necrosis factor alpha. J Exp Med. 1995 May 1;181(5):1615–1621. doi: 10.1084/jem.181.5.1615. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fong T. A., Mosmann T. R. The role of IFN-gamma in delayed-type hypersensitivity mediated by Th1 clones. J Immunol. 1989 Nov 1;143(9):2887–2893. [PubMed] [Google Scholar]
- Gazzinelli R. T., Wysocka M., Hayashi S., Denkers E. Y., Hieny S., Caspar P., Trinchieri G., Sher A. Parasite-induced IL-12 stimulates early IFN-gamma synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol. 1994 Sep 15;153(6):2533–2543. [PubMed] [Google Scholar]
- Gomez A. M., Bullock W. E., Taylor C. L., Deepe G. S., Jr Role of L3T4+ T cells in host defense against Histoplasma capsulatum. Infect Immun. 1988 Jul;56(7):1685–1691. doi: 10.1128/iai.56.7.1685-1691.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Graybill J. R. Histoplasmosis and AIDS. J Infect Dis. 1988 Sep;158(3):623–626. doi: 10.1093/infdis/158.3.623. [DOI] [PubMed] [Google Scholar]
- Lane T. E., Wu-Hsieh B. A., Howard D. H. Gamma interferon cooperates with lipopolysaccharide to activate mouse splenic macrophages to an antihistoplasma state. Infect Immun. 1993 Apr;61(4):1468–1473. doi: 10.1128/iai.61.4.1468-1473.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lin S. H., Medoff G., Kobayashi G. S. Effects of amphotericin B on macrophages and their precursor cells. Antimicrob Agents Chemother. 1977 Jan;11(1):154–160. doi: 10.1128/aac.11.1.154. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Newman S. L., Gootee L. Colony-stimulating factors activate human macrophages to inhibit intracellular growth of Histoplasma capsulatum yeasts. Infect Immun. 1992 Nov;60(11):4593–4597. doi: 10.1128/iai.60.11.4593-4597.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Orange J. S., Wolf S. F., Biron C. A. Effects of IL-12 on the response and susceptibility to experimental viral infections. J Immunol. 1994 Feb 1;152(3):1253–1264. [PubMed] [Google Scholar]
- Powrie F., Menon S., Coffman R. L. Interleukin-4 and interleukin-10 synergize to inhibit cell-mediated immunity in vivo. Eur J Immunol. 1993 Nov;23(11):3043–3049. doi: 10.1002/eji.1830231147. [DOI] [PubMed] [Google Scholar]
- Seder R. A., Kelsall B. L., Jankovic D. Differential roles for IL-12 in the maintenance of immune responses in infectious versus autoimmune disease. J Immunol. 1996 Oct 1;157(7):2745–2748. [PubMed] [Google Scholar]
- Smith J. G., Magee D. M., Williams D. M., Graybill J. R. Tumor necrosis factor-alpha plays a role in host defense against Histoplasma capsulatum. J Infect Dis. 1990 Dec;162(6):1349–1353. doi: 10.1093/infdis/162.6.1349. [DOI] [PubMed] [Google Scholar]
- Tripp C. S., Kanagawa O., Unanue E. R. Secondary response to Listeria infection requires IFN-gamma but is partially independent of IL-12. J Immunol. 1995 Oct 1;155(7):3427–3432. [PubMed] [Google Scholar]
- Wu-Hsieh B. Relative susceptibilities of inbred mouse strains C57BL/6 and A/J to infection with Histoplasma capsulatum. Infect Immun. 1989 Dec;57(12):3788–3792. doi: 10.1128/iai.57.12.3788-3792.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhou P., Sieve M. C., Bennett J., Kwon-Chung K. J., Tewari R. P., Gazzinelli R. T., Sher A., Seder R. A. IL-12 prevents mortality in mice infected with Histoplasma capsulatum through induction of IFN-gamma. J Immunol. 1995 Jul 15;155(2):785–795. [PubMed] [Google Scholar]
