Spermidine synthase is required for virulence of Leishmania donovani

Caslin Gilroy, Tamara Olenyik, Sigrid C. Roberts, Buddy Ullman

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Genetic lesions in the polyamine biosynthetic pathway of Leishmania donovani, the causal agent of visceral leishmaniasis, are conditionally lethal mutations that render the insect vector form of the parasite auxotrophic for polyamines. Recently, we have demonstrated that a Δodc L. donovani null mutant lacking ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, was profoundly compromised in its ability to infect mice, indicating that ODC is essential for the infectious mammalian stage of the parasite and further validating the enzyme as a possible drug target. To assess whether other components of the polyamine biosynthetic pathway were also essential for parasite virulence, a cell line deficient in spermidine synthase (SPDSYN), the enzyme that converts putrescine to spermidine, was created by double-targeted gene replacement within a virulent L. donovani background. This Δspdsyn strain was auxotrophic for polyamines, required spermidine for growth in its insect vector form, and was adversely impacted in its ability to infect mice. These findings establish that SPDSYN, like ODC, is essential for maintaining a robust infection in mammals and indicate that pharmacologic inhibition of SPDSYN, and perhaps all components of the polyamine biosynthetic pathway, is a valid therapeutic strategy for the treatment of visceral and, potentially, other forms of leishmaniasis.

Original languageEnglish (US)
Pages (from-to)2764-2769
Number of pages6
JournalInfection and Immunity
Volume79
Issue number7
DOIs
StatePublished - Jul 2011

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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    Gilroy, C., Olenyik, T., Roberts, S. C., & Ullman, B. (2011). Spermidine synthase is required for virulence of Leishmania donovani. Infection and Immunity, 79(7), 2764-2769. https://doi.org/10.1128/IAI.00073-11