Sphingosine-1-phosphate signaling in Leishmania donovani infection in macrophages.

• Published in: PLOS Neglected Tropical Diseases
• Main Authors: Mohd Arish, Atahar Husein, Rahat Ali, Shams Tabrez, Farha Naz, Mohammad Zulfazal Ahmad, Abdur Rub
• Format: Article in Journal/Newspaper
• Language: English
• Published: Public Library of Science (PLoS) 2018
• Subjects: Arctic medicine. Tropical medicine; RC955-962; Public aspects of medicine; RA1-1270; Arctic
• Online Access: https://doi.org/10.1371/journal.pntd.0006647; https://doaj.org/article/ab8acbced4c644278a66e82746c40f89

BACKGROUND:Sphingosine-1-phosphate (S1P) is a crucial regulator of a wide array of cellular processes, such as apoptosis, cell proliferation, migration, and differentiation, but its role in Leishmania donovani infection is unknown. METHODOLOGY/ PRINCIPAL FINDINGS:In the present study, we observed that L. donovani infection in THP-1 derived macrophages (TDM) leads to decrease in the expression of S1pr2 and S1pr3 at mRNA level. We further observed that Leishmania infection inhibits the phosphorylation of sphingosine kinase 1 (sphK1) in a time-dependent manner. Exogenous S1P supplementation decreases L. donovani induced ERK1/2 phosphorylation and increases p38 phosphorylation in TDM, resulting in a decrease in the intracellular parasite burden in a dose-dependent manner. On the other hand, sphK inhibition by DMS increases ERK1/2 phosphorylation leading to increased IL-10 and parasite load. To gain further insight, cytokines expression were checked in S1P supplemented TDM and we observed increase in IL-12, while decrease IL-10 expression at mRNA and protein levels. In addition, treatment of antagonist of S1PR2 and S1PR3 such as JTE-013 and CAY10444 respectively enhanced Leishmania-induced ERK1/2 phosphorylation and parasite load. CONCLUSIONS:Our overall study not only reports the significant role of S1P signaling during L. donovani infection but also provides a novel platform for the development of new drugs against Leishmaniasis.