Enhanced Sensitivity of Tumor Necrosis Factor/Lymphotoxin-a±De®cient Mice to Cryptococcus neoformans Infection despite Increased Levels

The cytokine network and infection severity were characterized during disseminated cryp-tococcosis in tumor necrosis factor (TNF) ± and lymphotoxin (Lt)-a±de®cient mice. On day 16, the fungus burden was higher and median survival time was reduced, as was polymor-phonuclear leukocyte in®ltrate in the brains of knockout mice. TNF/Lt-a±de®cient mice had lower levels of interleukin (IL)±6 in lungs and brains, IL-1b, and the chemokine KC in brain and spleen and of the chemokine monocyte chemoattractant protein (MCP)±1 in spleen than control animals. In contrast, higher levels of IL-6, IL-10, and MCP-1 in plasma and higher levels of IL-12, interferon (IFN)±g, and nitrite/nitrate were found in all compartments of TNF/Lt-a±de®cient mice. These data con®rm that TNF or Lt-a is a key cytokine for the anticryptococcal response and demonstrate its major role for the induction of IL-1b, IL-6, and KC in the brain; however, its presence is not a prerequisite for IL-12, IFN-g, and nitrite/ nitrate production. The yeast Cryptococcus neoformans is responsible for infec-tion mainly in immunocompromised persons, such as those with AIDS [1]. The severity of the infection is related to th