Oral putrescine restores virulence of ornithine decarboxylase-deficient Leishmania donovani in mice.

Abstract

Administration of putrescine as a 1% solution in the drinking water ameliorated the profound loss of virulence exhibited by ornithine decarboxylase (ODC) deficient Leishmania donovani in mice. Furthermore, supplying α-difluoromethylornithine, an ODC inhibitor, at 2% in the drinking water reduced but did not eliminate infection with wild type L. donovani in the mouse model. Taken collectively, these findings: (1) demonstrate that oral putrescine can access the phagolysosome of macrophages in which the parasite resides in mice; (2) establish that the loss of virulence due to the Δodc lesion is a consequence of the inability of the mutant parasite to synthesize sufficient polyamines de novo; (3) imply that the L. donovani amastigote cannot access host polyamines in sufficient amounts for survival and growth; (4) and validate ODC as a drug target, although oral administration of DFMO is an unlikely therapeutic paradigm for visceral leishmaniasis.

• Authors: Tamara Olenyik, Caslin Gilroy, Buddy Ullman
• Journal: Molecular and biochemical parasitology (Mol Biochem Parasitol) Vol. 176 Issue 2 Pg. 109-11 (Apr 2011) ISSN: 1872-9428 [Electronic] Netherlands
• PMID: 21182873 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Ornithine Decarboxylase Inhibitors
• Water
• Ornithine Decarboxylase
• Putrescine
• Eflornithine

Topics

• Administration, Oral
• Animals
• Disease Models, Animal
• Eflornithine (pharmacology, therapeutic use)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Female
• Leishmania donovani (drug effects, genetics, metabolism)
• Leishmaniasis, Visceral (drug therapy, parasitology)
• Macrophages (drug effects, metabolism)
• Mice
• Mice, Inbred BALB C
• Molecular Targeted Therapy
• Organisms, Genetically Modified (genetics, metabolism)
• Ornithine Decarboxylase (genetics, metabolism)
• Ornithine Decarboxylase Inhibitors
• Phagosomes (drug effects, metabolism)
• Putrescine (metabolism, pharmacology)
• Virulence (drug effects, genetics)
• Water (chemistry)