Protozoan parasites of the genus Leishmania are the causative agents for a group of serious diseases (known as Leishmaniasis) infecting 10-12 million people worldwide. Current drugs for leishmaniasis are plagued with low efficacy and high toxicity. With resistance on the rise and no safe vaccine available, there is an urgent need to maintain a steady stream of new drugs and potential drug targets. The PI's long term goal is to decipher the molecular strategy utilized by Leishmania parasites to thrive in sandflies and mammals. Advancement in the fundamental mechanism of pathogenesis can lead to new and improved treatments. In mammalian cells, sphingoid bases (SBs) and their phosphorylated derivatives are powerful signaling molecules regulating a plethora of essential pathways. Recent studies demonstrate that Leishmania parasites possess a very active SB metabolism with important yet poorly defined functions. The objective of this application is to elucidate the vital roles of SB metabolism in Leishmania proliferation and virulence. Formulated on the basis of strong preliminary studies, the central hypothesis is that SB metabolism is required for the adaptation of Leishmania parasites to the harsh environment in mammals, the removal of toxic metabolites, and the synthesis of essential phospholipids. Rationale for the proposed research is that a better understanding of this critically important and somewhat dangerous pathway will provide novel insight into parasite-host interaction and uncover new clues to control leishmaniasis.
Two specific aims will be undertaken to test the central hypothesis:
aim 1 is to elucidate the crucial roles of sphingosine kinase (a key enzyme in SB metabolism) in Leishmania;
and aim 2 is to determine why Leishmania needs ethanolamine phosphate (an intermediate in SB metabolism) to survive.
Each aim will explore one branch of the SB metabolic pathway in Leishmania. Genetic knockout mutants and their complemented controls will be generated and characterized using molecular, cellular, and biochemical approaches. Successful completion of these studies will significantly improve our understanding of SB metabolism in Leishmania and the function of lipid metabolites in general. This project is highly significant because in addition to the exciting new knowledge, a number of novel drug targets may emerge at the conclusion of these studies.

Public Health Relevance

Leishmania parasites infect 10-12 million people worldwide causing a spectrum of devastating diseases known as leishmaniasis. Current drugs are inadequate and no safe vaccine is available. This project will investigate an essential metabolic pathway in Leishmania, which may ultimately lead to new drugs and drug targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI099380-01A1
Application #
8439599
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Mcgugan, Glen C
Project Start
2012-12-10
Project End
2017-11-30
Budget Start
2012-12-10
Budget End
2013-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$335,749
Indirect Cost
$100,749
Name
Texas Tech University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041367053
City
Lubbock
State
TX
Country
United States
Zip Code
79409
Xu, Wei; Hsu, Fong-Fu; Baykal, Eda et al. (2014) Sterol biosynthesis is required for heat resistance but not extracellular survival in leishmania. PLoS Pathog 10:e1004427
Zhang, Ou; Hsu, Fong-Fu; Xu, Wei et al. (2013) Sphingosine kinase A is a pleiotropic and essential enzyme for Leishmania survival and virulence. Mol Microbiol 90:489-501