Abstract
Polyamines are metabolites that play important roles in rapidly proliferating cells, and recent studies have highlighted their critical nature in Leishmania parasites. However, little is known about the function of polyamines in parasites. To address this question, we assessed the effect of polyamine depletion in Leishmania donovani mutants lacking ornithine decarboxylase (Δodc) or spermidine synthase (Δspdsyn). Intracellular putrescine levels depleted rapidly in Δodc mutants and accumulated in Δspdsyn mutants, while spermidine levels were maintained at low but stable levels in both cell lines. Putrescine depletion in the Δodc mutants led to cell rounding, immediate cessation of proliferation, and loss of viability, while putrescine-rich Δspdsyn mutants displayed an intermediate proliferation phenotype and were able to arrest in a quiescent-like state for 6 weeks. Supplementation of Δodc mutants with spermidine had little effect on cell proliferation and morphology but enabled parasites to persist for 14 weeks. Thus, putrescine is not only essential as precursor for spermidine formation but also critical for parasite proliferation, morphology, and viability.
Highlights
Parasites of the genus Leishmania cause a variety of devastating diseases in humans and domestic animals worldwide
We have examined the consequences of polyamine depletion in L. donovani Δodc and Δspdsyn gene deletion mutants to better understand the functions of polyamines in Leishmania
We have previously shown that trypanothione levels in starved L. donovani Δodc and Δspdsyn parasites plummet over time (Jiang et al 1999; Roberts et al 2001), it is unknown whether this is due to a lack of trypanothione formation or conversion of trypanothione to spermidine
Summary
Parasites of the genus Leishmania cause a variety of devastating diseases in humans and domestic animals worldwide. The spectrum of leishmaniasis ranges from cutaneous ulcerative lesions to fatal visceralizing infections, and affects annually an estimated 12 million people worldwide (Kedzierski 2011). Among diseases of parasitic origin, visceral leishmaniasis is the second leading cause of mortality in humans (Alvar et al 2012; Bern et al 2008; Kaye and Scott 2011). Due to the absence of effective vaccines, chemotherapy offers the only avenue of defense against leishmaniasis (Kaye and Scott 2011; Kedzierski et al 2009; Muller 2007). The currently available small arsenal of drugs used to treat leishmaniasis is far from ideal due to a lack of selectivity and emergence of drug resistance
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