title: Early parasite containment is decisive for resistance to Leishmania major infection.
abstract: 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)-gamma 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-gamma, 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.
authors.affiliation: Institute for Clinical Microbiology and Immunology, University of Erlangen-Nürnberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Laskay
authors.forename: A
authors.initials: A
authors.lastname: Diefenbach
authors.forename: M
authors.initials: M
authors.lastname: Röllinghoff
authors.forename: W
authors.initials: W
authors.lastname: Solbach
mesh_terms: D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016054:DNA, Protozoan / Q000032:analysis; D005260:Female; D007371:Interferon-gamma / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D018320:Leishmania major / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000517:prevention & control*; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D008969:Molecular Sequence Data; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D016054:DNA, Protozoan; D007371:Interferon-gamma