Physiological consequences of drug resistance in Leishmania and their relevance for chemotherapy

Abstract

In the early twentieth century, infectious diseases were a leading cause of death worldwide. Through the following years, morbidity and mortality caused by infectious diseases decreased considerably in the developed world, but not in the developing world, where infectious diseases remain an important reason for concern. For example, leishmaniosis has become into a serious Third World problem. This is mainly due to an increasing frequency of drug-resistance in Leishmania and an enhanced risk of co-infection with HIV. Drug-resistance is usually associated with an increased expression of specific P-glycoproteins involved in membrane transport. The present review summarizes information which shows that drug-resistance is also associated with changes in physiological events such as parasite infectivity, incorporation of metabolites, xenobiotics conjugation and traffic, intracellular metabolism, host-parasite interaction, parasite cell shape and promastigote-amastigote differentiation. Furthermore, these events may change in a coordinated manner. An understanding of these physiological events may be helpful for designing chemotherapeutic approaches to multiple cellular targets, identifying strategies to circumvent Leishmania drug-resistance and succesfully treating leishmaniosis.

Figure 1

The Leishmania life cycle. The Leishmania life cycle begins when the vertebrate host is bitten by the infected insect. Then the inoculated parasites are phagocyted by the reticuloendothelial cells, the intracellular parasites replicate, and eventually burst free from the infected macrophages, spreading the disease within the mammal host. As a new insect bites an infected vertebrate host, it swallows infected macrophages, the parasites are then released, differentiate into promastigotes, migrate into the midgut, become metacyclic (infective parasites) during the next four to seven days and migrate to the cardial valve ready to be re-inoculated into a vertebrate host.

Figure 2

Physiological events associated with drug-resistance in Leishmania. The physiological events associated with drug-resistance in Leishmania include changes in P-gp expression, parasite infectivity (lipophosphoglycan, acid phosphatase and meta-1 expression), incorporation of metabolites fundamental for the parasite survival (folates and nucleosides), xenobiotics conjugation and extrusion (trypanothione and Cyb expression), intracellular metabolism (dihydrofolate reductase-thymidylate synthetase, N-acetylglucosamine-1-transferase and pterin transferase), host-parasite interaction (membrane fluidity) and parasite cell shape and promastigote-amastigote differentiation (tubulin phosphorylation). Black arrows indicate whether a given parameter is increased or decreased in the resistant parasite.