Regulation of infection with Histoplasma capsulatum by TNFR1 and -2.
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.
Allendoerfer
R
R
Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Deepe
G S
GS
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D016207:Cytokines / Q000032:analysis; D006658:Histoplasma / Q000276:immunology* / Q000302:isolation & purification; D006660:Histoplasmosis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D016130:Immunophenotyping; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000008:administration & dosage; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008172:Lung Diseases, Fungal / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II
D015703:Antigens, CD; D016207:Cytokines; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D009569:Nitric Oxide; D007371:Interferon-gamma