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Early parasite containment is decisive for resistance to Leishmania major infection
T Laskay1, A Diefenbach, M Röllinghoff
1Institute for Clinical Microbiology and Immunology, University of Erlangen-Nürnberg, Germany.
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.
Insights
Early spread of Leishmania major parasites is controlled by the innate immune system in resistant mice. Natural killer cells and interferon-gamma are crucial for preventing dissemination and developing a protective T cell response.
Area of Science:
- Immunology
- Parasitology
- Infectious Disease
Background:
- Leishmania major infection causes disease ranging from self-healing to fatal visceral leishmaniasis.
- Susceptibility to Leishmania major varies significantly between mouse strains, indicating a genetic basis for resistance.
- The early events following infection are critical in determining disease outcome.
Purpose of the Study:
- To investigate the early dissemination patterns of Leishmania major in different mouse strains.
- To identify the immune mechanisms responsible for controlling parasite spread in the initial phase of infection.
- To determine the role of innate and adaptive immune cells in early Leishmania major containment.
Main Methods:
- Subcutaneous infection of various mouse strains (BALB/c, C57BL/6, CBA/J, C3H/HeJ) with Leishmania major.
- Monitoring parasite dissemination to lymph nodes and visceral organs.
- Depletion of specific immune cells (NK1.1+, CD4+, CD8+) and cytokine neutralization (interferon-gamma).
- Infection experiments in severe-combined immunodeficient mice.
Main Results:
- Susceptible BALB/c mice showed rapid parasite dissemination within 10-24 hours to multiple organs.
- Resistant mouse strains (C57BL/6, CBA/J, C3H/HeJ) contained parasites locally for at least 3 days.
- Depletion of natural killer cells or neutralization of interferon-gamma in resistant mice led to parasite dissemination similar to susceptible mice.
- T cell depletion did not affect parasite dissemination kinetics in any strain.
- Experiments in severe-combined immunodeficient mice confirmed the role of natural killer cells and interferon-gamma, independent of T cells.
Conclusions:
- Early containment of Leishmania major is mediated by the innate immune system, primarily natural killer cells and interferon-gamma.
- This early innate immune response is strongly associated with the resistant phenotype.
- Local parasite restriction in the pre-T cell phase is crucial for developing a protective T cell response and successful infection outcome.