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

Abstract

The cytokine network and infection severity were characterized during disseminated cryptococcosis in tumor necrosis factor (TNF)- and lymphotoxin (Lt)-α-deficient mice. On day 16, the fungus burden was higher and median survival time was reduced, as was polymorphonuclear leukocyte infiltrate in the brains of knockout mice. TNF/Lt-α-deficient mice had lower levels of interleukin (IL)-6 in lungs and brains, IL-1β, 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)-γ, and nitrite/nitrate were found in all compartments of TNF/Lt-α-deficient mice. These data confirm that TNF or Lt-α is a key cytokine for the anticryptococcal response and demonstrate its major role for the induction of IL-1β, IL-6, and KC in the brain; however, its presence is not a prerequisite for IL-12, IFN-γ, and nitrite/nitrate production.