Macrophage microbicidal mechanisms in vivo: Reactive nitrogen versus oxygen intermediates in the killing of intracellular visceral Leishmania donovani

To determine the relative contributions of respiratory burst-derived reacti ve oxygen intermediates (ROI) versus reactive nitrogen intermediates (RNI) to macrophage-mediated intracellular host defense, mice genetically deficie nt in these mechanisms were challenged with Leishmania donovani, a protozoa n that selectively parasitizes visceral tissue macrophages. During the earl y stage of liver infection at wk 2, both respiratory burst-deficient gp91(p hox-/-) (X-linked chronic granulomatous disease [X-CGD]) mice and inducible nitric oxide synthase (iNOS) knockout (KO) mice displayed comparably incre ased susceptibility. Thereafter, infection was unrestrained in mice lacking iNOS but was fully controlled in X-CGD mice. Mononuclear cell influx into infected liver foci in X-CGD and iNOS KO mice was also overtly impaired at wk 2. However, granuloma assembly in parasitized tissue eventually develope d in both hosts but with divergent effects: mature granulomas were function ally active (leishmanicidal) in X-CGD mice but inert in iNOS-deficient anim als. These results suggest that (a) ROI and RNI probably act together in th e early stage of intracellular infection to regulate both tissue recruitmen t of mononuclear inflammatory cells and the initial extent of microbial rep lication, (b) RNI alone are necessary and sufficient for eventual control o f visceral infection, and (c) although mature granulomas have traditionally been associated with control of such infections, these structures fail to limit intracellular parasite replication in the absence of iNOS.