Visceral leishmaniasis in mice devoid of tumor necrosis factor and response to treatment - PubMed (original) (raw)

Visceral leishmaniasis in mice devoid of tumor necrosis factor and response to treatment

H W Murray et al. Infect Immun. 2000 Nov.

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.

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Figures

FIG. 1

FIG. 1

Course of L. donovani infection in livers of TNF KO (solid circles) and WT control mice (open circles). Results are from four experiments and indicate means ± standard errors of the means for 9 to 14 mice per group at weeks 2, 4, and 6 and for 3 mice per group at weeks 1 and 8. Observations of TNF KO mice ended at week 6 since 50% had died by week 8 (see Fig. 3). Differences in mean LDUs for KO versus WT mice were significant (P < 0.05) at weeks 2 and 4 but not at week 1 or week 6 (P < 0.05).

FIG. 2

FIG. 2

Liver histologic response to L. donovani 2 to 4 weeks after infection in WT controls (a) and TNF KO mice (b to f). (a and b) Week 2. WT mice (a) show normal developing granulomas (arrow) at sites of parasitized Kupffer cells; in contrast, in KO mice (b), there is no cellular response at parasitized foci (arrows). (c) Week 3. Rapid granuloma development in KO mice. (d and e) Week 4. KO mice show destructive inflammation with few recognizable granulomas, widespread areas of necrosis (N), and abundant cellular debris (d). Necrotic areas in panel d are ringed by partially preserved tissue containing large masses of intracellular amastigotes (arrows), also shown in panel e. (f) Week 3. Near absence of inflammatory changes in KO mice treated with AmB during the previous week. Magnifications, ×315 (a, b, and f), ×200 (c and d), and ×500 (e).

FIG. 3

FIG. 3

Survival after L. donovani infection in untreated (A) and AmB-treated mice (B). (A) Results are from two experiments in which a total of 18 WT controls (squares) and 20 TNF KO mice (circles) were infected but were not given antileishmanial treatment. (B) Results are from a single experiment in which infected TNF KO mice were (i) left untreated (open circles; n = 12 mice), (ii) given three AmB injections during weeks 2 to 3 only (hatched circles; n = 8), or (iii) treated similarly with AmB during weeks 2 to 3 and then given once-weekly AmB during weeks 4 to 7 (filled circles; n = 8).

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