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 capsulation. 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 or 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.