Sphingolipid Biosynthesis as an Antileishmanial Target and the Confounding Effects of Genome Plasticity

Abstract

Leishmania parasites cause devastating diseases in tropical areas around the world. With a lack of vaccine, treatment relies entirely on the current drugs in the market which have several limitations, including severe side effects and emerging resistance. These are major concerns worldwide which has led to the use of genomic and proteomic approaches for the detection and characterization of new targets to help formulate newer, better drugs.

Sphingolipids are major components of the plasma and intracellular membranes, playing an essential role in maintaining structural integrity as well as being involved in cell signalling functions. Due to this, sphingolipid metabolism is very tightly regulated to maintain balance of the sphingolipidome, allowing the generation of sphingolipids when needed and to degrade toxic sphingoid bases and ceramides to avoid accumulation. Many enzymes within the sphingolipid biosynthetic pathway are employed in this homeostasis, with dysregulation of within this pathway linked to diseases such as hereditary sensory neuropathy, type 1 caused by a mutation in serine palmitoyl transferase (SPT). In Leishmania spp, mutations and genetic manipulation of the enzymes within this pathway results in loss of parasite viability and infectivity. Targeting sphingosine kinase, a key enzyme within the sphingolipid pathway with a divergent structure compared with the human orthologue, as well as other enzymes within the pathway shows the genome to be highly plastic as previously reported. However, when studying genes which caused detrimental effects such as LCB2, probing the pathway genetically has been showed to result in many off-target genetic changes which has impact on the final clone generated and studied. A greater understanding of Leishmania genome plasticity has been gained and evidence of Leishmania parasites genetically adapting to conform to wanted genotype is shown in the ΔLmLCB2-/- population. Overall, these results suggest a need for the monitoring of genome stability in the clones generated and the essentiality of the sphingolipid biosynthetic pathway for Leishmania drug target.