Regulation of infection with Histoplasma capsulatum by TNFR1 and -2.

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-alpha 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-gamma and TNF-alpha levels in the lungs. In contrast, IFN-gamma 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.

• Authors: R Allendoerfer, G S Deepe Jr
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 165 Issue 5 Pg. 2657-64 (Sep 01 2000) ISSN: 0022-1767 [Print] United States
• PMID: 10946295 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antigens, CD
• Cytokines
• Receptors, Tumor Necrosis Factor
• Receptors, Tumor Necrosis Factor, Type I
• Receptors, Tumor Necrosis Factor, Type II
• Nitric Oxide
• Interferon-gamma

Topics

• Animals
• Antigens, CD (genetics, physiology)
• Cytokines (analysis)
• Histoplasma (immunology, isolation & purification)
• Histoplasmosis (genetics, immunology, microbiology, pathology)
• Immunophenotyping
• Injections, Intraperitoneal
• Interferon-gamma (administration & dosage)
• Lung (immunology, metabolism, microbiology, pathology)
• Lung Diseases, Fungal (genetics, immunology, microbiology, pathology)
• Macrophages, Alveolar (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nitric Oxide (biosynthesis)
• Receptors, Tumor Necrosis Factor (deficiency, genetics, physiology)
• Receptors, Tumor Necrosis Factor, Type I
• Receptors, Tumor Necrosis Factor, Type II