The Role of Polyamines for Proliferation, Survival, and Infectivity of the Protozoan Parasite Leishmania donovani

Abstract

A better understanding of parasite biology and host‐parasite interactions is critical for the development of much needed new therapeutic strategies against the neglected tropical disease leishmaniasis, which affects an estimated 12 million people annually. Polyamines are metabolites that play central roles in the biology of all eukaryotes, and recent studies have highlighted their critical nature in Leishmania parasites. In Leishmania, the polyamine biosynthetic pathway consists of four enzymes: arginase (ARG), ornithine decarboxylase (ODC), spermidine synthase (SPD), and S‐adenosylmethionine decarboxylase (ADOMETDC). These enzymes sequentially generate ornithine, putrescine and spermidine. We have generated a complete set of gene deletion mutants in Leishmania donovani (Δarg, Δodc, LdΔspd, and Δadometdc), in order to evaluate the polyamine biosynthetic enzymes as therapeutic targets and to study the functions of polyamines. In vivo studies revealed surprising differences in infectivity phenotypes, with the Δodc deletion exhibiting the most profound reduction in infectivity. In vitro studies showed that the gene deletion mutants depend on the provision of downstream metabolites to survive. An evaluation of cell growth between the different cell lines uncovered that the only vital role of ornithine is as precursor for polyamine synthesis. However, putrescine, which has previously been postulated to be merely a substrate for spermidine formation, has additional essential functions. Our studies revealed that putrescine is especially important for replication and proliferation. Both putrescine and spermidine were essential for cell survival, but the provision of either polyamine alone allowed parasites to enter a quiescent‐like state for several weeks. Future studies utilizing the gene deletion mutants will continue to elucidate the functions of polyamines for cellular proliferation, survival, and persistence.Support or Funding InformationNational Institute of Allergy and Infectious Disease Grant AI041622This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.