NITRIC OXIDE-MEDIATED ANTIPLASMODIAL ACTIVITY IN HUMAN AND MURINE HEPATOCYTES INDUCED BY GAMMA-INTERFERON AND THE PARASITE ITSELF - ENHANCEMENT BY EXOGENOUS TETRAHYDROBIOPTERIN

Expression of inducible nitric oxide (NO) synthase has been shown to i nhibit the development of several pathogens, including fungi, bacteria , parasites, and viruses. However, there is still controversy as to wh ether this effector mechanism can inhibit the development of human pat hogens. We now report that gamma interferon (IFN-gamma) induces the el imination of Plasmodium falciparum-infected primary human hepatocytes from cultures and that the antimalarial activity is dependent on NO. I nfection with the parasite alone in the absence of added IFN-gamma cau sed a 10-fold increase in NO formation. Both spontaneous inhibition an d IFN-gamma-induced inhibition of Plasmodium yoelii-infected murine he patocytes were increased with the addition of the NO synthase cofactor tetrahydrobiopterin, or sepiapterin, which is converted to tetrahydro biopterin. These results indicate that under in vitro conditions the p arasite itself provides a signal that triggers induction of the NO pat hway in human and murine hepatocytes and that NO formation in infected hepatocytes is limited by tetrahydrobiopterin availability.