Enhanced sensitivity of tumor necrosis factor/lymphotoxin-alpha-deficient mice to Cryptococcus neoformans infection despite increased levels of nitrite/nitrate, interferon-gamma, and interleukin-12

The cytokine network and infection severity were characterized during disse minated cryptococcosis in tumor necrosis factor (TNF)- and lymphotoxin (Lt) -alpha-deficient mice. On day 16, the fungus burden was higher and median s urvival time was reduced, as was polymorphonuclear leukocyte infiltrate in the brains of knockout mice. TNF/Lt-alpha-deficient mice had lower levels o f interleukin (IL)-6 in lungs and brains, IL-beta, and the chemokine KC in brain and spleen and of the chemokine monocyte chemoattractant protein (MCP )-1 in spleen than control animals. Ln contrast, higher levels of IL-6, IL- 10, and MCP-I in plasma and higher levels of IL-12, interferon (IFN)-gamma, and nitrite/nitrate were found in all compartments of TNF/Lt-alpha-deficie nt mice. These data confirm that TNF or Lt-alpha is a key cytokine for the anticryptococcal response and demonstrate its major role for the induction of IL-1 beta, IL-6, and KC in the brain; however, its presence is not a pre requisite for IL-12, IFN-gamma, and nitrite/ nitrate production.