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Control of Leishmania major infection in mice lacking TNF receptors
M Nashleanas1, S Kanaly, P Scott
1University of Pennsylvania School of Veterinary Medicine, Philadelphia 19104, USA.
Abstract:
TNF participates in the induction of nitric oxide (NO) production and macrophage activation, leading to the elimination of intracellular pathogens. We previously found that TNF receptor p55-deficient mice (TNFRp55-/-) control replication of Leishmania major in vivo but fail to resolve their lesions. Here we report that mice lacking the p75 receptor (TNFRp75-/-) or both receptors (TNFRp55p75-/-), also control parasite replication, albeit mice lacking the p55 receptor (either TNFRp55-/- or TNFRp55p75-/-) are delayed in their elimination of L. major compared with controls. All TNF receptor-deficient mice developed a Thl-type immune response and up-regulated inducible NO synthase (iNOS) mRNA gene expression in lesions during infection. Thus, neither TNF receptor appears to be absolutely required for NO production or elimination of L. major in vivo. In vitro, however, while macrophages from naive TNFRp75-/- mice could be activated to produce NO and kill L. major, we observed a defect in NO production and parasite killing by resident peritoneal macrophages from naive TNFRp55-/- or TNFRp55p75-/- mice. However, when macrophages were elicited with leishmanial Ag from 4-wk-infected TNFRp55-/- or TNFRp55p75-/- mice, they produced NO and were leishmanicidal. These data suggest that the TNFRp75 plays no essential role in L. major infection in mice and that the p55 receptor may be required for optimal macrophage activation. However, the results also show that a mechanism exists by which macrophages can be primed in vivo during L. major infection to produce NO and kill L. major in the absence of signaling through either of the TNF receptors.
Insights
Tumor necrosis factor (TNF) receptors are not essential for controlling Leishmania major infection in mice. However, the p55 receptor is crucial for optimal macrophage activation and parasite elimination.
Area of Science:
- Immunology
- Molecular Biology
- Pathogen-Host Interactions
Background:
- Tumor necrosis factor (TNF) is vital for macrophage activation and nitric oxide (NO) production, crucial for eliminating intracellular pathogens like Leishmania major.
- Previous studies showed TNF receptor p55-deficient mice control parasite replication but exhibit delayed lesion resolution.
Purpose of the Study:
- To investigate the roles of TNF receptor p55 and p75 in Leishmania major infection and macrophage activation.
- To determine if TNF receptors are essential for NO production and parasite elimination in vivo and in vitro.
Main Methods:
- Comparative analysis of Leishmania major infection in wild-type, TNFRp55-/-, TNFRp75-/-, and TNFRp55p75-/- mice.
- Assessment of parasite replication, lesion development, Th1 immune response, and inducible NO synthase (iNOS) mRNA expression.
- In vitro studies on NO production and Leishmania major killing by macrophages from different mouse strains.
Main Results:
- All TNF receptor-deficient mice controlled parasite replication, but TNFRp55 deficiency led to delayed elimination of L. major.
- Th1 immune response and iNOS mRNA expression were observed in all deficient mice.
- In vitro, naive TNFRp55-/- macrophages showed impaired NO production and parasite killing, which was restored upon in vivo priming.
- TNFRp75 deficiency had no significant impact on L. major infection outcomes.
Conclusions:
- The TNFRp75 plays a non-essential role in L. major infection.
- The TNFRp55 receptor is required for optimal macrophage activation and efficient elimination of L. major.
- A compensatory mechanism allows for NO production and parasite killing in macrophages even without TNF receptor signaling during infection.