Protective effect of neoglycoprotein-Conjugated muramyl dipeptide against leishmania donovani infection: The role of cytokines

Kakali Sarkar, Pijush K. Das

Research output: Contribution to journalArticle

Abstract

Active targeting of muramyl dipeptide (MDP) to macrophages was studied by conjugation with the neoglycoprotein, mannosyl human serum albumin (mannose-HSA) using visceral leishmaniasis as the model macrophage disease. Conjugation did not decrease the affinity of the neoglycoprotein for macrophage mannose receptor. Mannose-HSA-MDP was 50 times more efficient than free MDP in inhibiting the growth of Leishmania donovani inside peritoneal macrophages. Moreover, in a 60-day murine model of visceral leishmaniasis, 95% of the spleen parasite burden was reduced by mannose-HSA-MDP at a dose of 0.5 mg/kg/day given for 4 days. Free MDP at a similar dose had very little effect. In vitro exposure of MDP caused enhanced generation of O2- by macrophages, whereas generation of nitric oxide (NO) was not induced. The elevated antileishmanial activity of MDP-treated macrophages in culture was abrogated by O2- scavengers. In contrast, considerably enhanced amounts of NO and O2- were generated from macrophages of mannose-HSA-MDP-treated animals, and their splenocytes secreted soluble factors providing all the signals required for the induction of NO biosynthesis. The increase in NO production was paralleled by a concomitant increase in antileishmanial activity, which was reversed by NO synthesis inhibitors. Splenocyte supernatants treated with anti-IFN-γ or anti-TNF-γ Abs suppressed inducible NO generation by macrophages. Moreover, i.v. administration of anti-IFN-γ and anti-TNF-α along with mannose-HSA-MDP greatly reduced protection against L. donovani infection. Neoglycoprotein-conjugated MDP, therefore, activated mouse macrophages in vivo to kill L. donovani, and this may depend on the physiologic generation of NO induced by IFN-γ and TNF-α.

Original languageEnglish (US)
Pages (from-to)5357-5365
Number of pages9
JournalJournal of Immunology
Volume158
Issue number11
StatePublished - Dec 1 1997

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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