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Abstract
Phosphatidylcholine (PC) is the most abundant type of phospholipids in eukaryotes constituting ~30% of total lipids in Leishmania. PC synthesis mainly occurs via the choline branch of the Kennedy pathway (choline ⇒ choline-phosphate ⇒ CDP-choline ⇒ PC) and the N-methylation of phosphatidylethanolamine (PE). In addition, Leishmania parasites can acquire PC and other lipids from the host or culture medium. In this study, we assessed the function and essentiality of choline ethanolamine phosphotransferase (CEPT) in Leishmania major which is responsible for the final step of the de novo synthesis of PC and PE. Our data indicate that CEPT is localized in the endoplasmic reticulum and possesses the activity to generate PC from CDP-choline and diacylglycerol. Targeted deletion of CEPT is only possible in the presence of an episomal CEPT gene in the promastigote stage of L. major. These chromosomal null parasites require the episomal expression of CEPT to survive in culture, confirming its essentiality during the promastigote stage. In contrast, during in vivo infection of BALB/c mice, these chromosomal null parasites appeared to lose the episomal copy of CEPT while maintaining normal levels of virulence, replication and cellular PC. Therefore, while the de novo synthesis of PC/PE is indispensable for the proliferation of promastigotes, intracellular amastigotes appear to acquire most of their lipids through salvage and remodeling.
Highlights
Leishmaniasis is caused by protozoan parasites of the genus Leishmania which alternate between extracellular promastigotes colonizing the midgut of sandflies and intracellular amastigotes residing in the macrophage of mammals (Alvar et al, 2012)
Our results demonstrate that choline ethanolamine phosphotransferase (CEPT) is indispensable for L. major promastigotes but not amastigotes, suggesting that intracellular parasites can fulfill their need for PC through lipid salvage/remodeling
L. major CEPT is encoded by a single copy gene on chromosome 36 (TritrypDB ID: LmjF36.5900) with well conserved, syntenic orthologs among other trypanosomatids
Summary
Leishmaniasis is caused by protozoan parasites of the genus Leishmania which alternate between extracellular promastigotes colonizing the midgut of sandflies and intracellular amastigotes residing in the macrophage of mammals (Alvar et al, 2012). The mitigation of leishmaniasis mainly depends on vector control and drugs (Croft and Olliaro, 2011). Understanding of how Leishmania parasites acquire essential cellular components may lead to new drug targets and improved treatments. Glycerophospholipids such as phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are among the most abundant types of lipids accounting for approximately 30% and 10% of total lipids in Leishmania, respectively (Zhang and Beverley, 2010; Zheng et al, 2010). Understanding the mechanism by which Leishmania acquire their PC and PE may reveal new ways to block their growth
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