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Mice lacking the TNF receptor p55 fail to resolve lesions caused by infection with Leishmania major, but control
L Q Vieira1, M Goldschmidt, M Nashleanas
1Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia 19104, USA.
Abstract:
TNF is involved in host resistance to several pathogens. Recently it was found that mice lacking the p55 receptor for TNF (TNFRp55 -/-) do not control growth of the intracellular bacteria, Listeria monocytogenes and Mycobacterium tuberculosis. Here we report that the course of infection in TNFRp55 -/- mice with another intracellular pathogen, the protozoan parasite Leishmania major, is also quite different from normal mice. TNFRp55 -/- mice developed larger lesions than control mice and failed to resolve these lesions. However, they were able to eliminate parasites within the lesions. Histologic analysis indicated that at late stages lesions from TNFRp55 -/- mice appeared similar to lesions associated with cutaneous graft-vs-host disease. Both TNFRp55 -/- and control mice developed a normal Th1-type response during infection. We also found that IFN-gamma-activated macrophages from TNFRp55 -/- mice produced nitric oxide and killed L. major in vitro, which correlated with the ability of TNFRp55 -/- mice to eliminate the parasites in vivo. The production of nitric oxide by macrophages from TNFRp55 -/- mice required the presence of the parasites, however, since in their absence TNF could only synergize with IFN-gamma for nitric oxide production when added to normal, but not TNFRp55 -/-, macrophages. These results indicate that neither macrophage microbicidal activity nor nitric oxide production is absolutely dependent on the p55 receptor for TNF. Furthermore, they uncover a previously undefined role for TNFRp55 in resolution of parasite-induced inflammatory lesions.
Insights
Mice lacking the p55 tumor necrosis factor receptor (TNFRp55-/-) developed larger lesions but still eliminated Leishmania major parasites. This suggests TNFRp55 is crucial for resolving parasite-induced inflammation, not parasite clearance.
Area of Science:
- Immunology
- Parasitology
- Cell Biology
Background:
- Tumor necrosis factor (TNF) plays a role in host resistance to pathogens.
- TNFRp55-/- mice exhibit impaired control of intracellular bacteria like Listeria monocytogenes and Mycobacterium tuberculosis.
- The specific role of TNFRp55 in Leishmania major infection was previously undefined.
Purpose of the Study:
- To investigate the role of the p55 receptor for TNF (TNFRp55) in Leishmania major infection.
- To determine if TNFRp55 is essential for controlling parasite growth and resolving inflammation.
Main Methods:
- Infection of TNFRp55-/- mice and control mice with Leishmania major.
- Lesion size and parasite burden assessment.
- Histologic analysis of lesions.
- In vitro assessment of macrophage nitric oxide production and parasite killing.
Main Results:
- TNFRp55-/- mice developed larger, unresolved lesions compared to controls.
- Despite larger lesions, TNFRp55-/- mice successfully eliminated Leishmania major parasites.
- Macrophages from TNFRp55-/- mice produced nitric oxide and killed parasites in vitro.
- Nitric oxide production by macrophages required parasite presence and was not absolutely dependent on TNFRp55.
Conclusions:
- TNFRp55 is not essential for macrophage microbicidal activity or nitric oxide production against Leishmania major.
- TNFRp55 plays a critical role in the resolution of parasite-induced inflammatory lesions.
- The findings reveal a novel function for TNFRp55 in managing inflammatory responses to intracellular pathogens.