Inhibiting the mammalian target of rapamycin as an adjunctive therapy for cerebral malaria

Malaria is an infectious disease caused by parasites of the Plasmodium spp . In endemic areas, in approximately 1% of cases, almost exclusively in young children, malaria becomes severe resulting in nearly seven hundred thousand deaths each year in Africa alone. Cerebral malaria (CM) is a common form of severe malaria and one for which we have no effective adjunctive therapy. The kinase, mammalian target of rapamycin (mTOR), through its regulation of cellular metabolism, is a central regulator of immune responses and drugs that inhibit the mTOR pathway have been shown to be antiparasitic, raising the possibility that mTOR inhibitors could be effective adjunctive therapies for CM. Here we show in a mouse model of CM, experimental CM (ECM), that the mTOR inhibitor rapamycin protects against ECM when administered within the first four days of infection. Treatment with rapamycin increased survival, blocked breakdown of the blood brain barrier and brain hemorrhaging, decreased influx of both CD4 + and CD8 + T cells into the brain and the accumulation of parasitized red blood cells in the brain. Remarkably, animals were protected against ECM even though rapamycin treatment significantly increased the inflammatory response induced by infection in both the brain and spleen and elevated the levels of peripheral parasitemia. These results open a new avenue for the development of highly selective adjunctive therapies for CM, by targeting pathways that regulate host and parasite metabolism.