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*
Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267; and
Veterans Affairs Hospital, Cincinnati, OH 45219
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-
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-
and
TNF- levels in the lungs. In contrast, IFN- 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.
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