TY - JOUR
T1 - Oral putrescine restores virulence of ornithine decarboxylase-deficient Leishmania donovani in mice
AU - Olenyik, Tamara
AU - Gilroy, Caslin
AU - Ullman, Buddy
N1 - Funding Information:
This investigation was supported in part by grant R 01 AI041622 from the National Institute of Allergy and Infectious Diseases .
PY - 2011/4
Y1 - 2011/4
N2 - 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.
AB - 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.
KW - Leishmania donovani
KW - Ornithine decarboxylase
KW - Polyamines
KW - Putrescine
KW - α-Difluoromethylornithine
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U2 - 10.1016/j.molbiopara.2010.12.004
DO - 10.1016/j.molbiopara.2010.12.004
M3 - Article
C2 - 21182873
AN - SCOPUS:79951676877
SN - 0166-6851
VL - 176
SP - 109
EP - 111
JO - Molecular and Biochemical Parasitology
JF - Molecular and Biochemical Parasitology
IS - 2
ER -