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Visceral leishmaniasis in mice devoid of tumor necrosis factor and response to treatment
H W Murray1, A Jungbluth, E Ritter
1Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA. hwmurray@mail.med.cornell.edu
Abstract:
Tumor necrosis factor (TNF)-deficient mice were challenged with Leishmania donovani to characterize TNF in the response of visceral intracellular infection to antileishmanial chemotherapy. In wild-type controls (i) liver infection peaked at week 2 and resolved, (ii) discrete liver granulomas developed at weeks 2 to 4 and involuted, and (iii) leishmanicidal responses to antimony (Sb), amphotericin B (AmB), and miltefosine were intact. In TNF knockout (KO) mice (i) initial liver infection was unrestrained, plateaued, and then declined somewhat by week 6, (ii) an absent early granulomatous reaction abruptly accelerated with striking tissue inflammation, widespread hepatic necrosis, and 100% mortality by week 10, and (iii) while the initial response to AmB and miltefosine was intact, killing induced by Sb therapy was reduced by >50%. Although initial AmB treatment during weeks 2 to 3 killed 98% of liver parasites, 75% of AmB-treated KO mice subsequently relapsed and died by week 12; however, additional maintenance AmB preserved long-term survival. These results for a model of visceral infection indicate that endogenous TNF is required early on to control intracellular L. donovani, support granuloma development, and mediate optimal initial effects of Sb and prevent relapse after ordinarily curative AmB treatment. A compensatory, TNF-independent antileishmanial mechanism developed in TNF KO mice; however, its effect was uncontrolled fatal inflammation. Chemotherapeutic elimination of the parasite stimulus reversed the hyperinflammatory response and preserved survival.
Insights
Tumor necrosis factor (TNF) is essential for controlling Leishmania donovani infection and supporting chemotherapy effectiveness. Its absence leads to fatal inflammation, highlighting TNF's critical role in visceral leishmaniasis.
Area of Science:
- Immunology
- Parasitology
- Pharmacology
Background:
- Visceral leishmaniasis is a severe parasitic infection.
- The role of tumor necrosis factor (TNF) in visceral leishmaniasis and its impact on chemotherapy remains incompletely understood.
- Understanding TNF's function is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of endogenous TNF in the host response to Leishmania donovani infection.
- To characterize the impact of TNF deficiency on antileishmanial chemotherapy efficacy.
- To elucidate the mechanisms underlying TNF-mediated protection and inflammation.
Main Methods:
- Utilized TNF-deficient (knockout) mice and wild-type controls challenged with Leishmania donovani.
- Assessed parasite burden, liver pathology, granuloma formation, and survival rates.
- Evaluated the efficacy of antileishmanial drugs including antimony, amphotericin B, and miltefosine.
Main Results:
- TNF knockout mice exhibited unrestrained initial infection and developed severe hepatic necrosis and 100% mortality.
- Granuloma formation was absent in TNF knockout mice, leading to uncontrolled inflammation.
- Chemotherapy efficacy was reduced, particularly for antimony, and amphotericin B treatment led to relapses without maintenance therapy.
Conclusions:
- Endogenous TNF is critical for controlling Leishmania donovani infection and granuloma development.
- TNF mediates the optimal efficacy of antimony and amphotericin B and prevents relapse.
- TNF deficiency results in fatal inflammation, underscoring its protective role in visceral leishmaniasis.