Pharmacy and Pharmaceutical Sciences
Parasites of the genus Leishmania cause a variety of devastating and often fatal diseases, ranging from cutaneous ulcerative lesions to fatal visceralizing infections that affect an estimated 12 million people worldwide. Unfortunately, vaccines are not available and the cturent arsenal of drugs used to treat leishmaniasis is far from ideal. Thus the need for new therapeutic targets and a better understanding of host-parasite interactions is urgent. One biochemical pathway that has been successfully exploited for the treatment of a related parasitic disease, African trypanosomiasis, is the polyamine biosynthetic pathway. In order to elucidate the polyamine biosynthetic pathway and to explore its potential as a therapeutic target in Leishmania, we have generated and characterized gene deletion mutants and polyamine enzyme overproducer strains. These studies revealed that the polyamine pathway in Leishmania is significantly different from that of the mammalian host and polyamines were found to be essential for parasite proliferation. Infectivity studies in macrophages and mice with gene deletion mutants revealed that at least two polyamine biosynthetic enzymes, ornithine decarboxylase and spermidine synthase, are necessary for Leishmania donovani to establish a successful infection. However, arginase gene deletion mutants of Leishmania mexicana are still capable of eliciting an infection, albeit at lower levels than wild type parasites. Ongoing studies address whether the disparities in infectivity are due to the loss of specific enzymes within the pathway or to differences between the two Leishmania species. Furthermore, the gene deletion mutants are useful tools to investigate the relative contribution of host and parasite polyamine biosynthetic enzymes in parasite infectivity. This chapter will summarize how genetic manipulations in Leishmania have advanced our understanding of the polyamine pathway and its role in host-parasite interactions.
Roberts, S. C. (2013). Genetic manipulation of Leishmania parasites facilitates the exploration of the polyamine biosynthetic pathway as a potential therapeutic target. In K.V. Urbano (Ed.), Advances in Genetics Research, Volume 10 (29-54). Hauppauge, NY: Nova Science Publishers.