Roles of endogenous gamma interferon and macrophage microbicidal mechanisms in host response to chemotherapy in experimental visceral leishmaniasis

In experimental visceral leishmaniasis, in which the tissue macrophage is t he target, in vivo responsiveness to conventional chemotherapy (pentavalent antimony [Sb]) requires a T-cell-dependent mechanism. To determine if this mechanism involves gamma interferon (IFN-gamma)-induced activation and/or specific IFN-gamma-regulated macrophage leishmanicidal mechanisms (generati on of reactive nitrogen or oxygen intermediates, we treated gene-deficient mice infected with Leishmania donovani, In IFN-gamma gene knockout (GKO) mi ce, Sb inhibited but did not kill intracellular L. donovaai (2% killing ver sus 76% in controls). Sb was active (>94% killing), however, in both induci ble nitric oxide synthase (iNOS) knockout (KO) and respiratory burst (phago cyte oxidase)-deficient chronic granulomatous disease (X-CGD) mice. Sb's ef ficacy was also maintained in doubly deficient animals (X-CCD mice treated with an iNOS inhibitor). In contrast to Sb, amphotericin B (AmB) induced hi gh-level killing in GKO mice; AmB was also fully active in iNOS KO and X-CG D animals. Although resolution of L, donovani infection requires iNOS, resi dual visceral infection remained largely suppressed in iNOS KO mice treated with Sb or AmB, These results indicate that endogenous IFN-gamma regulates the leishmanicidal response to Sb and achieves this effect via a pathway u nrelated to the macrophage's primary microbicidal mechanisms. The role of I FN-gamma is selective, since it is not a cofactor in the response to AmB. T reatment with either Sb or AmB permits an iNOS-independent mechanism to eme rge and control residual intracellular L, donovani infection.