Leishmania donovani infection in scid mice: lack of tissue response and in vivo macrophage activation correlates with failure to trigger natural killer cell-derived gamma interferon production. Infect. Immun

Infection of immunocompetent mice with Leishmania donovani is characterized by the development of a tissue granulomatous response, in vivo macrophage activation, and a predominantly Thl-type CD4+ T-cell response. To determine whether a recently described T-cell-independent pathway ofgamma interferon (IFN-y) production involving the coUlaboration of macrophages and natural killer (NK) ceUs contributed to this pattern of events, we have investigated the responses of scid mice to L. donovani infection. The multiplication of parasites in the livers ofscid mice progressed at a rate equivalent to that seen in BALB/c mice over the first 14 days of infection, but by day 28 scid mice had a fivefold-higher parasite burden. This infection was not, however, accompanied by any demonstrable histological response in the liver or by elevated major histocompatibility complex class H expression on splenic macrophages. In vitro, L. donovani was unable to trigger IFN'y production from scid spleen cell cultures under conditions which allowed efficient triggering by bacterial stimuli. Although L. donovani also failed to stimulate the release of tumor necrosis factor, an important macrophage-derived cofactor for IFN-y secretion by NK cells, exogenous recombinant tumor necrosis factor alpha could not restore the IFN-y response. Even with the potent synergistic effect of exogenous interleukin-2, L. donovwani was unable to stimulate this pathway to the same extent as Listeria monocytogenes. Indeed, L. donovani inhibited the response to L. monocytogenes in a dose-dependent fashion. Experiment