Degradation of host sphingomyelin is essential for Leishmania virulence.

In eukaryotes, sphingolipids (SLs) are important membrane components and powerful signaling molecules. In Leishmania, the major group of SLs is inositol phosphorylceramide (IPC), which is common in yeast and Trypanosomatids but absent in mammals. In contrast, sphingomyelin is not synthesized by Leis...

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Autores principales:	Ou Zhang, Mattie C Wilson, Wei Xu, Fong-Fu Hsu, John Turk, F Matthew Kuhlmann, Yingwei Wang, Lynn Soong, Phillip Key, Stephen M Beverley, Kai Zhang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/f0b840a2689847e685d37266dfde24fe
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spelling	oai:doaj.org-article:f0b840a2689847e685d37266dfde24fe2021-11-25T05:48:27ZDegradation of host sphingomyelin is essential for Leishmania virulence.1553-73661553-737410.1371/journal.ppat.1000692https://doaj.org/article/f0b840a2689847e685d37266dfde24fe2009-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20011126/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374In eukaryotes, sphingolipids (SLs) are important membrane components and powerful signaling molecules. In Leishmania, the major group of SLs is inositol phosphorylceramide (IPC), which is common in yeast and Trypanosomatids but absent in mammals. In contrast, sphingomyelin is not synthesized by Leishmania but is abundant in mammals. In the promastigote stage in vitro, Leishmania use SL metabolism as a major pathway to produce ethanolamine (EtN), a metabolite essential for survival and differentiation from non-virulent procyclics to highly virulent metacyclics. To further probe SL metabolism, we identified a gene encoding a putative neutral sphingomyelinase (SMase) and/or IPC hydrolase (IPCase), designated ISCL (Inositol phosphoSphingolipid phospholipase C-Like). Despite the lack of sphingomyelin synthesis, L. major promastigotes exhibited a potent SMase activity which was abolished upon deletion of ISCL, and increased following over-expression by episomal complementation. ISCL-dependent activity with sphingomyelin was about 20 fold greater than that seen with IPC. Null mutants of ISCL (iscl(-)) showed modest accumulation of IPC, but grew and differentiated normally in vitro. Interestingly, iscl(-) mutants did not induce lesion pathology in the susceptible BALB/c mice, yet persisted indefinitely at low levels at the site of infection. Notably, the acute virulence of iscl(-) was completely restored by the expression of ISCL or heterologous mammalian or fungal SMases, but not by fungal proteins exhibiting only IPCase activity. Together, these findings strongly suggest that degradation of host-derived sphingomyelin plays a pivotal role in the proliferation of Leishmania in mammalian hosts and the manifestation of acute disease pathology.Ou ZhangMattie C WilsonWei XuFong-Fu HsuJohn TurkF Matthew KuhlmannYingwei WangLynn SoongPhillip KeyStephen M BeverleyKai ZhangPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 5, Iss 12, p e1000692 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Ou Zhang Mattie C Wilson Wei Xu Fong-Fu Hsu John Turk F Matthew Kuhlmann Yingwei Wang Lynn Soong Phillip Key Stephen M Beverley Kai Zhang Degradation of host sphingomyelin is essential for Leishmania virulence.
description	In eukaryotes, sphingolipids (SLs) are important membrane components and powerful signaling molecules. In Leishmania, the major group of SLs is inositol phosphorylceramide (IPC), which is common in yeast and Trypanosomatids but absent in mammals. In contrast, sphingomyelin is not synthesized by Leishmania but is abundant in mammals. In the promastigote stage in vitro, Leishmania use SL metabolism as a major pathway to produce ethanolamine (EtN), a metabolite essential for survival and differentiation from non-virulent procyclics to highly virulent metacyclics. To further probe SL metabolism, we identified a gene encoding a putative neutral sphingomyelinase (SMase) and/or IPC hydrolase (IPCase), designated ISCL (Inositol phosphoSphingolipid phospholipase C-Like). Despite the lack of sphingomyelin synthesis, L. major promastigotes exhibited a potent SMase activity which was abolished upon deletion of ISCL, and increased following over-expression by episomal complementation. ISCL-dependent activity with sphingomyelin was about 20 fold greater than that seen with IPC. Null mutants of ISCL (iscl(-)) showed modest accumulation of IPC, but grew and differentiated normally in vitro. Interestingly, iscl(-) mutants did not induce lesion pathology in the susceptible BALB/c mice, yet persisted indefinitely at low levels at the site of infection. Notably, the acute virulence of iscl(-) was completely restored by the expression of ISCL or heterologous mammalian or fungal SMases, but not by fungal proteins exhibiting only IPCase activity. Together, these findings strongly suggest that degradation of host-derived sphingomyelin plays a pivotal role in the proliferation of Leishmania in mammalian hosts and the manifestation of acute disease pathology.
format	article
author	Ou Zhang Mattie C Wilson Wei Xu Fong-Fu Hsu John Turk F Matthew Kuhlmann Yingwei Wang Lynn Soong Phillip Key Stephen M Beverley Kai Zhang
author_facet	Ou Zhang Mattie C Wilson Wei Xu Fong-Fu Hsu John Turk F Matthew Kuhlmann Yingwei Wang Lynn Soong Phillip Key Stephen M Beverley Kai Zhang
author_sort	Ou Zhang
title	Degradation of host sphingomyelin is essential for Leishmania virulence.
title_short	Degradation of host sphingomyelin is essential for Leishmania virulence.
title_full	Degradation of host sphingomyelin is essential for Leishmania virulence.
title_fullStr	Degradation of host sphingomyelin is essential for Leishmania virulence.
title_full_unstemmed	Degradation of host sphingomyelin is essential for Leishmania virulence.
title_sort	degradation of host sphingomyelin is essential for leishmania virulence.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/f0b840a2689847e685d37266dfde24fe
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Degradation of host sphingomyelin is essential for Leishmania virulence.

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