Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Plasmodium falciparum growth is regulated by Sphingosine 1 phosphate produced by Host Erythrocyte Membrane Sphingosine kinase 1

Raj Kumar Sah, Monika Saini, Soumya Pati, View ORCID ProfileShailja Singh
doi: https://doi.org/10.1101/756502
Raj Kumar Sah
Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Monika Saini
Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, IndiaDepartment of Life Sciences, School of Natural Sciences, Shiv Nadar University, Greater Noida, India
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Soumya Pati
Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Greater Noida, India
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shailja Singh
Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Shailja Singh
  • For correspondence: shailja.jnu@gmail.com shailja.singh@jnu.ac.in
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Sphingosine-1-phosphate (S1P) a bioactive lipid is produced in its primary reservoir, erythrocytes by an enzyme Sphingosine kinase-1 (SphK-1). The activation of such kinases and the subsequent S1P generation and secretion in the blood serum represent a major regulator of many cellular signaling cascades. Orthologue of sphingosine kinases 1 and 2 (SphK-1 and 2) that catalyze the phosphorylation of sphingosine generating S1P are not present in malaria parasite. The malaria parasite, Plasmodium falciparum, is an intracellular obligatory organism that reside in the human erythrocyte during its blood stage life cycle and orchestrates many metabolic interactions with host for its survival. Given the regulatory role of S1P, we targeted host SphK-1 by a generic pharmacological inhibitor N,N-Dimethyl-sphingosine (DMS) and analyzed growth of intra-erythrocytic parasite. We found that reducing S1P levels by inhibiting host SphK-1 activity led to halted parasite growth and ultimately cell death. Reduced intracellular S1P levels were attributed to decreased glycolysis marked by the low uptake of glucose by parasite and by less production of lactate, a byproduct of glycolysis. Reduced glycolysis was mediated by decrease translocation of the glycolytic enzyme, Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) to the cytosol of infected erythrocytes and cell death. Knocking down of erythrocyte SphK-1 is not lethal to the host and being a host encoded enzyme, targeting it with safe and specific drugs will not lead to the problem of resistance; thus, SphK-1 represents a potent target for the development of therapeutics against intra-erythrocytic P. falciparum.

Author Summary Erythrocytes membrane enzyme Sphingosine kinase-1 (SphK-1) produces Sphingosine-1-phosphate (S1P) a bioactive lipid by phosphorylation of Sphingosine (Sph). S1P generated by activation of SphK is prosurvival signal and regulate cell growth. The malaria parasite, Plasmodium falciparum, is an intracellular obligatory pathogen that reside in erythrocyte during its blood stage life cycle and orchestrates many metabolic interactions with its host erythrocytes for survival. Orthologue of SphK-1/ 2 are not present in malaria parasite, therefore treatment with SphK inhibitor targeted host SphK-1 and led to reduced S1P level. The reduction in host S1P led to halted parasite growth and cell death. Furthermore, reduced erythrocyte S1P levels led to decreased glycolysis marked by the low uptake of glucose by parasite and by less production of lactate. Erythrocyte SphK-1 being a host encoded enzyme, is resistance safe and represents a potent target for the development of therapeutics against intra-erythrocytic P. falciparum.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted September 03, 2019.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Plasmodium falciparum growth is regulated by Sphingosine 1 phosphate produced by Host Erythrocyte Membrane Sphingosine kinase 1
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
Share
Plasmodium falciparum growth is regulated by Sphingosine 1 phosphate produced by Host Erythrocyte Membrane Sphingosine kinase 1
Raj Kumar Sah, Monika Saini, Soumya Pati, Shailja Singh
bioRxiv 756502; doi: https://doi.org/10.1101/756502
Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Plasmodium falciparum growth is regulated by Sphingosine 1 phosphate produced by Host Erythrocyte Membrane Sphingosine kinase 1
Raj Kumar Sah, Monika Saini, Soumya Pati, Shailja Singh
bioRxiv 756502; doi: https://doi.org/10.1101/756502

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Cell Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (1545)
  • Biochemistry (2500)
  • Bioengineering (1757)
  • Bioinformatics (9729)
  • Biophysics (3929)
  • Cancer Biology (2990)
  • Cell Biology (4235)
  • Clinical Trials (135)
  • Developmental Biology (2653)
  • Ecology (4129)
  • Epidemiology (2033)
  • Evolutionary Biology (6933)
  • Genetics (5243)
  • Genomics (6532)
  • Immunology (2208)
  • Microbiology (7012)
  • Molecular Biology (2784)
  • Neuroscience (17412)
  • Paleontology (127)
  • Pathology (432)
  • Pharmacology and Toxicology (712)
  • Physiology (1068)
  • Plant Biology (2516)
  • Scientific Communication and Education (647)
  • Synthetic Biology (835)
  • Systems Biology (2699)
  • Zoology (439)