NITRIC-OXIDE - CYTOKINE-REGULATION OF NITRIC-OXIDE IN HOST-RESISTANCETO INTRACELLULAR PATHOGENS

To discover how nitric oxide (NO) synthesis is controlled in different tissues as cells within these tissues combat intracellular pathogens, we examined three distinctively different experimental murine models designed for studying parasite-host interactions: macrophage killing o f Leishmania major; nonspecific protection against tularemia (Francise lla tularensis) by My cobacterium bovis (BCG); and specific vaccine-in duced protection against hepatic malaria with Plasmodium berghei. Each model parasite and host system provides information on the source and role of NO during infection and the factors that induce or inhibit it s production. The in vitro assay for macrophage antimicrobial activity against L. major identified cytokines involved in regulating NO-media ted killing of this intracellular protozoan. L. major induced the prod uction of two competing cytokines in infected macrophages: (I) the par asite activated the gene for tumor necrosis factor (TNF), and producti on of TNF protein was enhanced by the presence of interferon-gamma (IF N-gamma). TNF then acted as a autocrine signal to amplify IFN-gamma-in duced production of NO; and (2) the parasite upregulated production of transforming growth factor-beta (TGF-beta), which blocked IFN-gamma-i nduced production of NO. Whether parasite-induced TNF (parasite destru ction) or TGF-beta (parasite survival) prevailed depended upon the pre sence and quantity of IFN-gamma at the time of infection. The relation ship between NO production in vivo and host resistance to infection wa s demonstrated with M bovis (BCG). These studies confirmed that both I FN-gamma and TNF are required for induction of NO-mediated nonspecific host defense in vivo. The presumed source of NO in these studies was the activated macrophage, however, other cells infected with parasites can also be stimulated to produce NO. In studying acquired immunity t o malaria induced by irradiated sporozoites, we found that IFN-gamma p rovided by malaria-specific CD8(+) T cells stimulated sporozoite-infec ted hepatocytes to produce NO for destruction of either infected hepat ocytes or the parasite, P. berghei, within these cells.