Erythrocyte sphingosine kinase regulates intraerythrocytic development of Plasmodium falciparum

Abstract The sphingolipid pool is key regulator of vital cellular functions in Plasmodium falciparum a causative agent for deadly malaria. Erythrocytes, the host for asexual stage of Plasmodium, are major reservoir for Sphingosine-1-phosphate (S1P). Erythrocyte possesses Sphingosine kinase (SphK) th...

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Autores principales:	Raj Kumar Sah, Soumya Pati, Monika Saini, Shailja Singh
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/123e994626d44f9b9f932feaf069c0f1
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spelling	oai:doaj.org-article:123e994626d44f9b9f932feaf069c0f12021-12-02T14:01:36ZErythrocyte sphingosine kinase regulates intraerythrocytic development of Plasmodium falciparum10.1038/s41598-020-80658-72045-2322https://doaj.org/article/123e994626d44f9b9f932feaf069c0f12021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80658-7https://doaj.org/toc/2045-2322Abstract The sphingolipid pool is key regulator of vital cellular functions in Plasmodium falciparum a causative agent for deadly malaria. Erythrocytes, the host for asexual stage of Plasmodium, are major reservoir for Sphingosine-1-phosphate (S1P). Erythrocyte possesses Sphingosine kinase (SphK) that catalyzed its biosynthesis from sphingosine (Sph). Since, Plasmodium lacks SphK homologous protein it can be envisaged that it co-opts sphingolipids from both intraerythrocytic as well as extracellular pools for its growth and development. Herein, by sphingosine-NBD probing, we report that infected erythrocytes imports Sph from extracellular pool, which is converted to S1P and thereby taken by P. falciparum. Next, by targeting of the SphK through specific inhibitor N,N-Dimethylsphingosine DMS, we show a reduction in erythrocyte endogenous S1P pool and SphK-phosphorylation that led to inhibition in growth and development of ring stage P. falciparum. Owing to the role of S1P in erythrocyte glycolysis we analyzed uptake of NBD-Glucose and production of lactate in DMS treated and untreated plasmodium. DMS treatment led to decreased glycolysis in Plasmodium. Interestingly the host free Plasmodium did not show any effect on glycolysis with DMS treatment indicating its host-mediated effect. Further to understand the in-vivo anti-plasmodial effects of exogenous and endogenous erythrocyte S1P level, Sphingosine-1-phosphate lyase (S1PL) inhibitor (THI), S1P and SphK-1 inhibitor (DMS), were used in Plasmodium berghei ANKA (PbA) mice model. DMS treatment led to reduction of endogenous S1P conferred significant decrease in parasite load, whereas the plasma level S1P modulated by (THI) and exogenous S1P have no effect on growth of Plasmodium. This suggested erythrocyte endogenous S1P pool is important for Plasmodium growth whereas the plasma level S1P has no effect. Altogether, this study provides insight on cellular processes regulated by S1P in P. falciparum and highlights the novel mechanistically distinct molecular target i.e. SphK-1.Raj Kumar SahSoumya PatiMonika SainiShailja SinghNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Raj Kumar Sah Soumya Pati Monika Saini Shailja Singh Erythrocyte sphingosine kinase regulates intraerythrocytic development of Plasmodium falciparum
description	Abstract The sphingolipid pool is key regulator of vital cellular functions in Plasmodium falciparum a causative agent for deadly malaria. Erythrocytes, the host for asexual stage of Plasmodium, are major reservoir for Sphingosine-1-phosphate (S1P). Erythrocyte possesses Sphingosine kinase (SphK) that catalyzed its biosynthesis from sphingosine (Sph). Since, Plasmodium lacks SphK homologous protein it can be envisaged that it co-opts sphingolipids from both intraerythrocytic as well as extracellular pools for its growth and development. Herein, by sphingosine-NBD probing, we report that infected erythrocytes imports Sph from extracellular pool, which is converted to S1P and thereby taken by P. falciparum. Next, by targeting of the SphK through specific inhibitor N,N-Dimethylsphingosine DMS, we show a reduction in erythrocyte endogenous S1P pool and SphK-phosphorylation that led to inhibition in growth and development of ring stage P. falciparum. Owing to the role of S1P in erythrocyte glycolysis we analyzed uptake of NBD-Glucose and production of lactate in DMS treated and untreated plasmodium. DMS treatment led to decreased glycolysis in Plasmodium. Interestingly the host free Plasmodium did not show any effect on glycolysis with DMS treatment indicating its host-mediated effect. Further to understand the in-vivo anti-plasmodial effects of exogenous and endogenous erythrocyte S1P level, Sphingosine-1-phosphate lyase (S1PL) inhibitor (THI), S1P and SphK-1 inhibitor (DMS), were used in Plasmodium berghei ANKA (PbA) mice model. DMS treatment led to reduction of endogenous S1P conferred significant decrease in parasite load, whereas the plasma level S1P modulated by (THI) and exogenous S1P have no effect on growth of Plasmodium. This suggested erythrocyte endogenous S1P pool is important for Plasmodium growth whereas the plasma level S1P has no effect. Altogether, this study provides insight on cellular processes regulated by S1P in P. falciparum and highlights the novel mechanistically distinct molecular target i.e. SphK-1.
format	article
author	Raj Kumar Sah Soumya Pati Monika Saini Shailja Singh
author_facet	Raj Kumar Sah Soumya Pati Monika Saini Shailja Singh
author_sort	Raj Kumar Sah
title	Erythrocyte sphingosine kinase regulates intraerythrocytic development of Plasmodium falciparum
title_short	Erythrocyte sphingosine kinase regulates intraerythrocytic development of Plasmodium falciparum
title_full	Erythrocyte sphingosine kinase regulates intraerythrocytic development of Plasmodium falciparum
title_fullStr	Erythrocyte sphingosine kinase regulates intraerythrocytic development of Plasmodium falciparum
title_full_unstemmed	Erythrocyte sphingosine kinase regulates intraerythrocytic development of Plasmodium falciparum
title_sort	erythrocyte sphingosine kinase regulates intraerythrocytic development of plasmodium falciparum
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/123e994626d44f9b9f932feaf069c0f1
work_keys_str_mv	AT rajkumarsah erythrocytesphingosinekinaseregulatesintraerythrocyticdevelopmentofplasmodiumfalciparum AT soumyapati erythrocytesphingosinekinaseregulatesintraerythrocyticdevelopmentofplasmodiumfalciparum AT monikasaini erythrocytesphingosinekinaseregulatesintraerythrocyticdevelopmentofplasmodiumfalciparum AT shailjasingh erythrocytesphingosinekinaseregulatesintraerythrocyticdevelopmentofplasmodiumfalciparum
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Erythrocyte sphingosine kinase regulates intraerythrocytic development of Plasmodium falciparum

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