Synthetic retinoid Am80 controls growth of intracellular Toxoplasma by inhibiting acquisition and synthesis of cholesterol in macrophages

Abstract

Because the obligate intracellular parasite Toxoplasma gondii lacks the ability to synthesize cholesterol, T. gondii needs to obtain cholesterol from host cells. Am80 is known to reduce the cellular cholesterol and lipid bodies in macrophages. In this study, we demonstrated that inhibition of acquisition and synthesis of cholesterol in macrophage cell line J774A.1 by a synthetic retinoid Am80 suppressed the growth of T. gondii. Am80 inhibited T. gondii-induced high levels of cellular cholesterol in J774A.1 cells while the level of cellular TAG was increased by treatment with the drug. Furthermore, the expression of LDLR was down regulated in the Am80-treated cells. Am80 reduced the expression of HMG-CoA reductase and ACAT1, and increased DGAT1 expression. These results suggest that cholesterol acquisition via LDLR and cholesterol synthesis is necessary for T. gondii growth though the roles of cellular TAG are still unknown. Finally, we studied the effect of Am80 in vivo. Mice treated with 1.0 mg/kg of Am80 ameliorated acute toxoplasmosis. Our findings support the notion that modulation of the lipid metabolism in host cells is a potential strategy for the treatment and prevention of toxoplasmosis.