Immune Regulation In Toxoplasmosis And Other Opportunist

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Abstract

Dendritic cell (DC) production of IL-12 is thought to be a major initiation step in host resistance to Toxoplasma gondii. However, over-production of this cytokine can be detrimental to the host resulting in severe tissue damage. Lipoxin A4 (LXA4) is a potent endogenous lipoxygenase-derived eicosanoid with antiinflammatory and proresolving properties. We have previously shown that supraphysiological levels of LXA4 are generated during T. gondii infection, which in turn reduces interleukin (IL) 12 production by dendritic cells, thus dampening Th1-type cell-mediated immune responses and host immunopathology. In this years work, we investigated the mechanism by which T. gondii's stimulates LXA4 biosynthesis. Proteomic analysis of T. gondii extract (soluble tachyzoite antigen [STAg]), which preserves the immunosuppressive and antiinflammatory activity of the parasite, yielded several peptide matches to known plant lipoxygenases. To investigate their potential enzymatic function, we incubated STAg with arachidonic acid and found using LC-UV-MS-MS?based lipidomics that the parasite extract generated the production of both 15-HETE and 5,15-diHETE, indicating that T. gondii carries 15-lipoxygenase(15-LO)activity. In addition, T. gondii tachyzoites (the rapidly multiplying and invasive stage of the parasite) generated LXA4 when provided with exogenous arachidonic acid. Local administration of a plant (soybean) lipoxygenase itself reduced neutrophilic infiltration in murine peritonitis, demonstrating that 15-lipoxygenase possesses antiinflammatory properties. Importantly, administration of a plant 15-lipoxygenase generated endogenous LXA4 and mimicked the suppression of IL-12 production by splenic dendritic cells observed after T. gondii infection or STAg administration. These findings suggest that T.gondii stimulates LXA4 production by augmenting 15-lipoxygenase levels in the host through its own sythesis of the enzyme. On a broader level our studies indicate that enzymes involved in eicosonoid synthesis expressed by a pathogen can interact with host biosynthetic circuits to generate lipoxins that act as endogenous "stop signals" suppressing the host immune response and limiting acute inflammation.