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Regulation of Infection with Histoplasma capsulatum by TNFR1 and -2

Ruth Allendoerfer and George S. Deepe Jr.
J Immunol September 1, 2000, 165 (5) 2657-2664; DOI: https://doi.org/10.4049/jimmunol.165.5.2657
Ruth Allendoerfer
*Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267; and
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George S. Deepe Jr.
*Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267; and
†Veterans Affairs Hospital, Cincinnati, OH 45219
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Abstract

The concerted action of several cytokines is necessary for resolution of both primary and secondary infection with Histoplasma capsulatum. Among the soluble factors that contribute to tissue sterilization, TNF-α stands as a central mediator of protective immunity to this fungus. In this study, we explored the regulation of protective immunity by TNFR1 and -2. In primary pulmonary infection, both TNFR1−/− and -2−/− mice manifested a high mortality after infection with H. capsulatum, although TNFR1−/− mice were more susceptible than TNFR2 −/− mice. Overwhelming infection in the former was associated with a pronounced decrement in the number of inflammatory cells in the lungs and elevated IFN-γ and TNF-α levels in the lungs. In contrast, IFN-γ levels were markedly decreased in TNFR2−/− mice, and treatment with this cytokine restored protective immunity. Lung macrophages from both groups of knockout mice released substantial amounts of NO. Upon secondary infection, TNFR2−/− mice survived rechallenge and cleared infection as efficiently as C57BL/6 animals. In contrast, mice given mAb to TNFR1 succumbed to reexposure, and the high mortality was accompanied by a significant increase in fungal burden in the lungs. Both IL-4 and IL-10 were elevated in the lungs of these mice. The results demonstrate the pivotal influence of TNFR1 and -2 in controlling primary infection and highlight the differences between these receptors for regulation reexposure histoplasmosis.

  • Received March 28, 2000.
  • Accepted June 14, 2000.
  • Copyright © 2000 by The American Association of Immunologists
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The Journal of Immunology: 165 (5)
The Journal of Immunology
Vol. 165, Issue 5
1 Sep 2000
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Regulation of Infection with Histoplasma capsulatum by TNFR1 and -2
Ruth Allendoerfer, George S. Deepe
The Journal of Immunology September 1, 2000, 165 (5) 2657-2664; DOI: 10.4049/jimmunol.165.5.2657

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Regulation of Infection with Histoplasma capsulatum by TNFR1 and -2
Ruth Allendoerfer, George S. Deepe
The Journal of Immunology September 1, 2000, 165 (5) 2657-2664; DOI: 10.4049/jimmunol.165.5.2657
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