{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:19Z","timestamp":1778544019351,"version":"3.51.4"},"reference-count":77,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2017,7,26]],"date-time":"2017-07-26T00:00:00Z","timestamp":1501027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["INT-76-BAS"],"award-info":[{"award-number":["INT-76-BAS"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The survival of intracellular protozoan parasite, <jats:italic>Leishmania donovani<\/jats:italic>, the causative agent of Indian visceral leishmaniasis (VL), depends on the activation status of macrophages. <jats:sc>l<\/jats:sc>-Arginine, a semi-essential amino acid plays a crucial regulatory role for activation of macrophages. However, the role of <jats:sc>l<\/jats:sc>-arginine transport in VL still remains elusive. In this study, we demonstrated that intra-macrophage survival of <jats:italic>L. donovani<\/jats:italic> depends on the availability of extracellular <jats:sc>l<\/jats:sc>-arginine. Infection of THP-1-derived macrophage\/human monocyte-derived macrophage (hMDM) with <jats:italic>Leishmania<\/jats:italic>, resulted in upregulation of <jats:sc>l<\/jats:sc>-arginine transport. While investigating the involvement of the transporters, we observed that <jats:italic>Leishmania<\/jats:italic> survival was greatly impaired when the transporters were blocked either using inhibitor or siRNA-mediated downregulation. CAT-2 was found to be the main isoform associated with <jats:sc>l<\/jats:sc>-arginine transport in <jats:italic>L. donovani<\/jats:italic>-infected macrophages. <jats:sc>l<\/jats:sc>-arginine availability and its transport regulated the host arginase in <jats:italic>Leishmania<\/jats:italic> infection. Arginase and inducible nitric oxide synthase (iNOS) expression were reciprocally regulated when assayed using specific inhibitors and siRNA-mediated downregulation. Interestingly, induction of iNOS expression and nitric oxide production were observed in case of inhibition of arginase in infected macrophages. Furthermore, inhibition of <jats:sc>l<\/jats:sc>-arginine transport as well as arginase resulted in decreased polyamine production, limiting parasite survival inside macrophages. <jats:sc>l<\/jats:sc>-arginine availability and transport regulated Th1\/Th2 cytokine levels in case of <jats:italic>Leishmania<\/jats:italic> infection. Upregulation of <jats:sc>l<\/jats:sc>-arginine transport, induction of host arginase, and enhanced polyamine production were correlated with increased level of IL-10 and decreased level of IL-12 and TNF-\u03b1 in <jats:italic>L. donovani<\/jats:italic>-infected macrophages. Our findings provide clear evidence for targeting the metabolism of <jats:sc>l<\/jats:sc>-arginine and <jats:sc>l<\/jats:sc>-arginine-metabolizing enzymes as an important therapeutic and prophylactic strategy to treat VL.<\/jats:p>","DOI":"10.3389\/fimmu.2017.00839","type":"journal-article","created":{"date-parts":[[2017,7,26]],"date-time":"2017-07-26T03:57:36Z","timestamp":1501041456000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":32,"title":["RETRACTED: l-Arginine Uptake by Cationic Amino Acid Transporter Promotes Intra-Macrophage Survival of Leishmania donovani by Enhancing Arginase-Mediated Polyamine Synthesis"],"prefix":"10.3389","volume":"8","author":[{"given":"Abhishek","family":"Mandal","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sushmita","family":"Das","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ajay","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saptarshi","family":"Roy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sudha","family":"Verma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayan 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