Toxoplasma gondii Triggers Granulocyte-Dependent Cytokine-Mediated Lethal Shock in d-Galactosamine-Sensitized Mice

To investigate the capacity of Toxoplasma gondii to induce cytokine-mediated toxicity, we employed a murine model of lethal shock in which hypersensitivity to microbial toxins is induced by d-galactosamine (d-Gal). Animals injected with d-Gal and tachyzoite lysate died within 12 to 24 h, whereas administration of d-Gal or lysate alone was nonlethal. Analyses of plasma cytokines revealed peaks of tumor necrosis factor (TNF) alpha and interleukin-12 (IL-12) 1 and 3 to 5 h after injection, respectively, and gradually rising levels of gamma interferon (IFN-γ) continuing until death. Nitric oxide (NO) levels in serum paralleled IFN-γ production. Transaminase assays revealed elevated levels of liver-associated enzymes in sera of lethally injected mice, indicating severe hepatic damage. Depletion of IL-12, TNF, IFN-γ, and NO rescued mice from the lethal effect of antigen (Ag) and d-Gal. T-cell-deficient animals remained sensitive to d-Gal and lysate, suggesting that T lymphocytes do not contribute to the response. Nevertheless, monoclonal antibody (MAb)-mediated granulocyte depletion completely abrogated d-Gal- and Ag-induced mortality and accompanying liver pathology. Finally, mice acutely infected with T. gondii displayed highly elevated NO and liver enzyme levels in serum immediately prior to death, and administration of anti-TNF MAb prolonged survival by approximately 24 h. Our results demonstrate that T. gondii induces lethal inflammatory cytokine shock in d-Gal-sensitized animals and suggest that a similar pathology may contribute to manifestations of acute toxoplasmosis.