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 infection, the parasites disseminated within 10‐24 h from the site of subcutaneous footpad infection in to the popliteal lymph node, spleen, lung, liver and bone marrow. Application of recombinant (r)IL‐12 prior to infection prevented the early dissemination of parasites into visceral 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. major infection, the parasites remained localized in the footpad and in the draining LN for 3 days without evidence of dissemination. In C57BL/6 mice, depletion of NK1.1⁺ cells or neutralization of interferon (IFN)‐γ prior to infection led to rapid parasite spreading with kinetics similar to those seen in susceptible animals. Depletion of either CD4⁺ or CD8⁺ T cells 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 parasite containment depends on natural killer cells and IFN‐γ, but is independent of T cells. The finding that all resistant mouse strains restrict the spread of the parasites within the first 24 h after infection strongly suggests that early parasite containment is closely associated with a resistant phenotype. The data show that local restriction 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 important role in the development of a protective T cell response.