Balancing de novo synthesis and salvage of lipids by Leishmania amastigotes

Zhang, Kai

doi:10.1016/j.mib.2021.07.004

Cited by 15 publications

(17 citation statements)

References 50 publications

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“…A recent study demonstrated the function and importance of choline ethanolamine phosphotransferase (CEPT) in Leishmania major, assessing its importance for the de novo synthesis of PC and PE [25]. For glycerophospholipids, sterols, and sphingolipids, studies have focused on elucidating the balance between promastigote L. major de novo synthesis and amastigote lipid salvage and remodeling [26].…”

Section: Introductionmentioning

confidence: 99%

Fatty Acid Profiles of Leishmania major Derived from Human and Rodent Hosts in Endemic Cutaneous Leishmaniasis Areas of Tunisia and Algeria

et al. 2022

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Leishmaniasis is a protozoal vector-borne disease that affects both humans and animals. In the Mediterranean Basin, the primary reservoir hosts of Leishmania spp. are mainly rodents and canids. Lipidomic approaches have allowed scientists to establish Leishmania spp. lipid profiles for the identification of cell stage specific biomarkers, drug mechanisms of action, and host immune response. Using an in silico approach of global network interaction between genes involved in fatty acid (FA) synthesis followed by the GC-MS approach, we were able to characterize the fatty acid profiles of L. major derived from human and rodent hosts. Our results revealed that the lipid profile of L. major showed similarities and differences with those already reported for other Leishmania species. Phospholipids are the predominant lipid class. FA composition of rodent parasites was characterized by a lower abundance of the precursor C18:2(n-6). One of the rodent clones, which also expressed the lowest lipid abundance in PL and TAG, was the least sensitive clone to the miltefosine drug and has the lowest infection efficiency. Our findings suggest that the lipid composition variation may explain the response of the parasite toward treatment and their ability to infect their host.

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Section: Introductionmentioning

confidence: 99%

Fatty Acid Profiles of Leishmania major Derived from Human and Rodent Hosts in Endemic Cutaneous Leishmaniasis Areas of Tunisia and Algeria

et al. 2022

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“…However, Leishmania sp. are known to take up and salvage a variety of host lipids including SM (McConville and Naderer 2011, Zhang 2021). This raised the possibility that any potential amastigote-stage SL requirement could be satisfied by swapping endogenous IPC by salvage with host SM.…”

Section: Discussionmentioning

confidence: 99%

“…However, Leishmania sp. are known to take up a variety of host lipids (53)(54)(55), and perhaps potential amastigote-stage SL requirements could be satisfied through uptake and metabolism of host SLs.…”

Section: Abundant Salvage Leads To Predominance Of Sm Over Ipc In Wt ...mentioning

confidence: 99%

“…However, Leishmania sp. are known to take up a variety of host lipids (54)(55)(56), and perhaps potential amastigote-stage SL requirements could be satisfied through uptake and metabolism of host SLs. MS analysis of purified amastigotes showed high levels of host SM in both WT and Δipcs -, with SM estimated to be about 7-fold more abundant than parasite IPC (estimated previously to be present at about 10 8 molecules/amastigote) (34).…”

Section: Minimal Impact Of Ipcs Deletion On Promastigotes In Vitromentioning

confidence: 99%

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Inositol phosphorlyceramide synthase null Leishmania major are viable and virulent in animal infections where salvage of host sphingomyelin predominates

Kuhlmann

Key

Hickerson

et al. 2022

Preprint

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Many pathogens synthesize inositolphosphorylceramide (IPC) as the major sphingolipid (SL), unlike the mammalian host where sphingomyelin or more complex SLs predominate. Thus, divergence between IPCS and mammalian sphingolipid synthases has prompted interest as a potential drug target. However, in the trypanosomatid protozoan Leishmania, promastigotes lacking de novo sphingolipid synthesis (∆spt2-) survive and remain virulent, as amastigotes salvage host sphingolipids and are still able to produce IPC. To further understand the role of IPC, we generated null IPCS mutants in L. major (Δipcs-). Unexpectedly and unlike fungi where IPCS is essential, Δipcs- was remarkably normal in culture and highly virulent in mouse infections. Both IPCS activity and IPC itself were absent in Δipcs- promastigotes and amastigotes, arguing against an alternative route of IPC synthesis. Notably, salvaged mammalian sphingomyelin was highly abundant in purified amastigotes from both WT and Δipcs-. Quantitative estimation showed SM to be about 5-fold more abundant than IPC in WT, suggesting that normally SM is the dominant amastigote SL. Analysis of the WT amastigote IPC ceramide anchor showed that it arose not from de novo synthesis by the parasite, but through catabolism of mammalian SLs, probably through the action of the parasite sphingomyelinase ISCL. These data suggest that SM salvage may account for the survival and virulence of Δipcs-, a finding which likely mitigates the suitability of IPCS as a chemotherapeutic target.

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“…However, Leishmania sp. are known to take up a variety of host lipids (54)(55)(56), and perhaps potential amastigote-stage SL requirements could be satisfied through uptake and metabolism of host SLs. MS analysis of purified amastigotes showed high levels of host SM J o u r n a l P r e -p r o o f 16 in both WT and Δipcs -, with SM estimated to be about 7-fold more abundant than parasite IPC (estimated previously to be present at about 10 8 molecules/amastigote) (34).…”

Section: Abundant Salvage Leads To Predominance Of Sm Over Ipc In Wt ...mentioning

confidence: 99%

Inositol phosphorylceramide synthase null Leishmania are viable and virulent in animal infections where salvage of host sphingomyelin predominates

Kuhlmann

Key

Hickerson

et al. 2022

Journal of Biological Chemistry

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Balancing de novo synthesis and salvage of lipids by Leishmania amastigotes

Cited by 15 publications

References 50 publications

Fatty Acid Profiles of Leishmania major Derived from Human and Rodent Hosts in Endemic Cutaneous Leishmaniasis Areas of Tunisia and Algeria

Fatty Acid Profiles of Leishmania major Derived from Human and Rodent Hosts in Endemic Cutaneous Leishmaniasis Areas of Tunisia and Algeria

Inositol phosphorlyceramide synthase null Leishmania major are viable and virulent in animal infections where salvage of host sphingomyelin predominates

Inositol phosphorylceramide synthase null Leishmania are viable and virulent in animal infections where salvage of host sphingomyelin predominates

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