EARLY PARASITE CONTAINMENT IS DECISIVE FOR RESISTANCE TO LEISHMANIA-MAJOR INFECTION

We investigated the early spread of Leishmania major in various mouse strains. In BALB/c mice, which are extremely vulnerable to L. major in fection, the parasites disseminated within 10-24 h from the site of su bcutaneous footpad infection in to the popliteal lymph node, spleen, l ung, liver and bone marrow Application of recombinant (r)IL-12 prior t o infection prevented the early dissemination of parasites into viscer al organs and the animals healed the infection. In three mouse strains tested, C57BL/6, CBA/J and C3H/HeJ, which are all resistant to L. maj or infection, the parasites remained localized in the footpad and in t he draining LN for 3 days without evidence of dissemination. In C57BL/ 6 mice, depletion of NK1.1(+) cells or neutralization of interferon (I FN)-gamma prior to infection led to rapid parasite spreading with kine tics similar to those seen in susceptible animals. Depletion of either CD4(+) or CD8(+) Tcells in vivo prior to infection did not alter the kinetics of dissemination in any mouse strain tested. Experiments with severe-combined immunodeficient mice provided further evidence that p arasite containment depends on natural killer cells and IFN-gamma, but is independent of T cells. The finding that all resistant mouse strai ns restrict the spread of the parasites within the first 24 h after in fection strongly suggests that early parasite containment is closely a ssociated with a resistant phenotype. The data show that local restric tion of parasites in the pre-T cell phase of the infection is mediated by the innate immune system and suggest that this function plays an i mportant role in the development of a protective T cell response.