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Infection and Immunity, November 2000, p. 6289-6293, Vol. 68, No. 11
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Visceral Leishmaniasis in Mice Devoid of Tumor Necrosis Factor and Response to Treatment

Henry W. Murray,1,* Achim Jungbluth,2 Erika Ritter,2 Christina Montelibano,1 and Michael W. Marino2

Department of Medicine, Weill Medical College of Cornell University,1 and Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center,2 New York, New York 10021

Received 20 April 2000/Returned for modification 13 June 2000/Accepted 2 August 2000

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.

* Corresponding author. Mailing address: Box 136, 1300 York Ave., New York, NY 10021. Phone: (212) 746-6330. Fax: (212) 746-6332. E-mail: hwmurray{at}mail.med.cornell.edu.

Infection and Immunity, November 2000, p. 6289-6293, Vol. 68, No. 11
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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