{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T18:48:26Z","timestamp":1776365306508,"version":"3.51.2"},"update-to":[{"DOI":"10.1371\/journal.pntd.0013102","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000}}],"reference-count":69,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001412","name":"Council of Scientific and Industrial Research, India","doi-asserted-by":"publisher","award":["13(9160-A)2021-Pool"],"award-info":[{"award-number":["13(9160-A)2021-Pool"]}],"id":[{"id":"10.13039\/501100001412","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001409","name":"Department of Science and Technology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","award":["IPA\/2020\/000007"],"award-info":[{"award-number":["IPA\/2020\/000007"]}],"id":[{"id":"10.13039\/501100001409","id-type":"DOI","asserted-by":"publisher"}]},{"name":"DPRP","award":["Project No. P\/569\/2016-1\/TDT"],"award-info":[{"award-number":["Project No. P\/569\/2016-1\/TDT"]}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator regulating apoptosis, proliferation, and immune responses. While S1Ps presence in\n                      <jats:italic>Leishmania donovani<\/jats:italic>\n                      phagolysosomes has been reported, the role of sphingosine kinases, especially SphK1, in parasite survival and host immune modulation remains underexplored. This study investigates the molecular and functional role of\n                      <jats:italic>L. donovani<\/jats:italic>\n                      SphK1 (\n                      <jats:italic>Ld<\/jats:italic>\n                      SphK1) and evaluates the antileishmanial potential of PF-543, a specific SphK1 inhibitor.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Ld<\/jats:italic>\n                      SphK1 and human SphK1 (\n                      <jats:italic>rh<\/jats:italic>\n                      SphK1) were cloned, expressed in\n                      <jats:italic>E. coli<\/jats:italic>\n                      , purified, and analyzed by SDS-PAGE. Enzymatic activity and inhibition by PF-543 were assessed using NBD-S1P-based fluorometric assays. Protein-ligand interactions were analyzed using Microscale Thermophoresis (MST) and validated\n                      <jats:italic>in silico<\/jats:italic>\n                      docking studies, which identified key species-specific differences in the inhibitor\u2019s active site.\n                      <jats:italic>Leishmania<\/jats:italic>\n                      promastigotes overexpressing\n                      <jats:italic>Ld<\/jats:italic>\n                      SphK1 were studied via confocal microscopy, and their viability and infectivity were assessed\n                      <jats:italic>in vitro<\/jats:italic>\n                      . THP-1 macrophages infected with\n                      <jats:italic>L. donovani<\/jats:italic>\n                      were treated with PF-543 alone or with Amphotericin B and analyzed by MTT assay, RT-PCR, Giemsa staining, ELISA and immunoblotting.\n                      <jats:italic>In vivo<\/jats:italic>\n                      efficacy was tested in\n                      <jats:italic>L. donovani<\/jats:italic>\n                      -infected Swiss mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>rLd<\/jats:italic>\n                      SphK1 (~102 kDa) and\n                      <jats:italic>rh<\/jats:italic>\n                      SphK1 (~50 kDa) were enzymatically active and significantly inhibited by PF-543. MST demonstrated specific, measurable binding of PF-543 to both orthologues (KD\u2009~\u200929\u03bcM under identical experimental conditions). In\n                      <jats:italic>L. donovani<\/jats:italic>\n                      SphK1 overexpressor\n                      <jats:italic>(Ld<\/jats:italic>\n                      SphKa) promastigotes, PF-543 inhibited SphK1 activity and reduced parasite infectivity, more than in wildtype\n                      <jats:italic>L. donovani<\/jats:italic>\n                      promastigotes. Notably, PF-543 treatment reduced parasite infectivity\n                      <jats:italic>in vitro<\/jats:italic>\n                      , lowered amastigote load by ~40%, and promoted a pro-inflammatory cytokine shift (\u2191IL-12,\u2009\u2191\u2009TNF-\u03b1,\u2009\u2193\u2009IL-10). Inhibition of ceramide synthesis and S1P supplementation revealed that S1P rescues ceramide-induced parasite death, implicating SphK1 in parasite survival. PF-543 and Amphotericin B demonstrated synergistic anti-parasitic effects both\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      , with &gt;90% reduction in parasite burden in mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      PF-543 exerts moderate direct inhibition of parasite SphK1 while prominently modulating host SphK1-dependent immune and apoptotic pathways, collectively restricting\n                      <jats:italic>Leishmania<\/jats:italic>\n                      survival. Rather than functioning as a parasite-selective inhibitor, PF-543 acts as a dual host\u2013parasite modulator. These findings provide proof-of-concept evidence that simultaneous targeting of sphingolipid signalling in both host and parasite can enhance anti-leishmanial efficacy and support further exploration of SphK-based combination therapeutic strategies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pntd.0013102","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T17:40:08Z","timestamp":1774028408000},"page":"e0013102","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Leishmania donovani Sphingosine Kinase 1 using PF-543 enhances immune response and limits parasite load"],"prefix":"10.1371","volume":"20","author":[{"given":"Evanka","family":"Madan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruby","family":"Bansal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jhalak","family":"Singhal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nishant","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika","family":"Saini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sadat","family":"Shafi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aashima","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5286-6605","authenticated-orcid":true,"given":"Shailja","family":"Singh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"issue":"5","key":"pntd.0013102.ref001","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0035671","article-title":"Leishmaniasis 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