{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:23:03Z","timestamp":1777422183322,"version":"3.51.4"},"reference-count":28,"publisher":"The Company of Biologists","issue":"9","license":[{"start":{"date-parts":[[2019,5,1]],"date-time":"2019-05-01T00:00:00Z","timestamp":1556668800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/501100001409","name":"Department of Science and Technology, Ministry of Science and Technology","doi-asserted-by":"publisher","award":["EMR\/2014\/000287"],"award-info":[{"award-number":["EMR\/2014\/000287"]}],"id":[{"id":"10.13039\/501100001409","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology","doi-asserted-by":"publisher","award":["BT\/PR10289\/BRB\/10\/1257\/2013"],"award-info":[{"award-number":["BT\/PR10289\/BRB\/10\/1257\/2013"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Academy of Sciences, India"},{"name":"Council\u00a0of\u00a0Scientific and Industrial Research, India"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,5,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Previously, we documented the role of the programmed death-1 (PD-1, also known as PDCD1) pathway in macrophage apoptosis and the downregulation of this signaling during infection by the intra-macrophage parasite Leishmania donovani. However, we also found that, during the late phase of infection, PD-1 expression was significantly increased without activating host cell apoptosis; here we show that inhibition of PD-1 led to markedly decreased parasite survival, along with increased production of TNF\u03b1, IL-12, reactive oxygen species (ROS) and nitric oxide (NO). Increased PD-1 led to inactivation of AKT proteins resulting in nuclear sequestration of FOXO-1. Transfecting infected cells with constitutively active FOXO-1 (CA-FOXO) led to increased cell death, thereby suggesting that nuclear FOXO-1 might be inactivated. Infection significantly induced the expression of SIRT1, which inactivated FOXO-1 through deacetylation, and its knockdown led to increased apoptosis. SIRT1 knockdown also significantly decreased parasite survival along with increased production of TNF\u03b1, ROS and NO. Administration of the SIRT1 inhibitor sirtinol (10\u2005mg\/kg body weight) in infected mice decreased spleen parasite burden and a synergistic effect was found with PD-1 inhibitor. Collectively, our study shows that Leishmania utilizes the SIRT1\/FOXO-1 axis for differentially regulating PD-1 signaling and, although they are interconnected, both pathways independently contribute to intracellular parasite survival.<\/jats:p>\n               <jats:p>This article has an associated First Person interview with the first author of the paper.<\/jats:p>","DOI":"10.1242\/jcs.226274","type":"journal-article","created":{"date-parts":[[2019,3,25]],"date-time":"2019-03-25T16:46:08Z","timestamp":1553532368000},"source":"Crossref","is-referenced-by-count":24,"title":["Crosstalk of PD-1 signaling with the SIRT1\/FOXO-1 axis during the progression of visceral leishmaniasis"],"prefix":"10.1242","volume":"132","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8053-1650","authenticated-orcid":false,"given":"Shalini","family":"Roy","sequence":"first","affiliation":[{"name":"CSIR-Indian Institute of Chemical Biology 1 Infectious Diseases and Immunology Division , , Kolkata 700032 , India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0710-3913","authenticated-orcid":false,"given":"Shriya","family":"Saha","sequence":"additional","affiliation":[{"name":"Calcutta University 2 Department of Biochemistry , , Kolkata 700019 , India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1586-0594","authenticated-orcid":false,"given":"Purnima","family":"Gupta","sequence":"additional","affiliation":[{"name":"Calcutta University 2 Department of Biochemistry , , Kolkata 700019 , India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2114-6469","authenticated-orcid":false,"given":"Anindita","family":"Ukil","sequence":"additional","affiliation":[{"name":"Calcutta University 2 Department of Biochemistry , , Kolkata 700019 , India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9452-7441","authenticated-orcid":false,"given":"Pijush K.","family":"Das","sequence":"additional","affiliation":[{"name":"CSIR-Indian Institute of Chemical Biology 1 Infectious Diseases and Immunology Division , , Kolkata 700032 , India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2019,5,2]]},"reference":[{"key":"2024061318305103700_JCS226274C1","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1189\/jlb.1001877","article-title":"Leishmania major-mediated prevention of programmed cell death induction in infected macrophages is associated with the repression of mitochondrial release of cytochrome c","volume":"76","author":"Akarid","year":"2004","journal-title":"J. Leukoc. Biol."},{"key":"2024061318305103700_JCS226274C2","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.1161\/01.RES.0000267723.65696.4a","article-title":"Sirt1 regulates aging and resistance to oxidative stress in the heart","volume":"100","author":"Alcendor","year":"2007","journal-title":"Circ. Res."},{"key":"2024061318305103700_JCS226274C3","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1016\/S0092-8674(00)80595-4","article-title":"Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor","volume":"96","author":"Brunet","year":"1999","journal-title":"Cell"},{"key":"2024061318305103700_JCS226274C4","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/j.tem.2009.03.008","article-title":"Caloric restriction, SIRT1 and longevity","volume":"20","author":"Cant\u00f3","year":"2009","journal-title":"Trends Endocrinol. Metab."},{"key":"2024061318305103700_JCS226274C5","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.bbrc.2008.11.110","article-title":"Resveratrol protects cardiomyocytes from hypoxia-induced apoptosis through the SIRT1-FoxO1 pathway","volume":"378","author":"Chen","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2024061318305103700_JCS226274C6","doi-asserted-by":"publisher","first-page":"e2115","DOI":"10.1038\/cddis.2016.33","article-title":"Attenuation of the programmed cell death-1 pathway increases the M1 polarization of macrophages induced by zymosan","volume":"7","author":"Chen","year":"2016","journal-title":"Cell Death Dis."},{"key":"2024061318305103700_JCS226274C7","doi-asserted-by":"publisher","first-page":"2136","DOI":"10.1128\/IAI.01589-06","article-title":"Leishmania donovani-induced ceramide as the key mediator of Akt dephosphorylation in murine macrophages: role of protein kinase Czeta and phosphatase","volume":"75","author":"Dey","year":"2007","journal-title":"Infect. Immun."},{"key":"2024061318305103700_JCS226274C8","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1093\/infdis\/jis771","article-title":"Successful therapy of visceral leishmaniasis with curdlan involves T-helper 17 cytokines","volume":"207","author":"Ghosh","year":"2013","journal-title":"J. Infect. Dis."},{"key":"2024061318305103700_JCS226274C9","doi-asserted-by":"publisher","first-page":"3887","DOI":"10.1002\/j.1460-2075.1992.tb05481.x","article-title":"Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death","volume":"11","author":"Ishida","year":"1992","journal-title":"EMBO J."},{"key":"2024061318305103700_JCS226274C10","doi-asserted-by":"publisher","first-page":"e1000431","DOI":"10.1371\/journal.ppat.1000431","article-title":"B7-H1 blockade increases survival of dysfunctional CD8(+) T cells and confers protection against Leishmania donovani infections","volume":"5","author":"Joshi","year":"2009","journal-title":"PLoS Pathog."},{"key":"2024061318305103700_JCS226274C11","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1189\/jlb.0909644","article-title":"MAPK-directed phosphatases preferentially regulate pro- and anti-inflammatory cytokines in experimental visceral leishmaniasis: involvement of distinct protein kinase C isoforms","volume":"88","author":"Kar","year":"2010","journal-title":"J. Leukoc. Biol."},{"key":"2024061318305103700_JCS226274C12","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1146\/annurev.immunol.26.021607.090331","article-title":"PD-1 and its ligands in tolerance and immunity","volume":"26","author":"Keir","year":"2008","journal-title":"Annu. Rev. Immunol."},{"key":"2024061318305103700_JCS226274C13","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1111\/j.1365-2567.2010.03382.x","article-title":"PD-1 negatively regulates interleukin-12 expression by limiting STAT-1 phosphorylation in monocytes\/macrophages during chronic hepatitis C virus infection","volume":"132","author":"Ma","year":"2011","journal-title":"Immunology"},{"key":"2024061318305103700_JCS226274C14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1042\/BJ20070140","article-title":"Sirtuins in mammals: insights into their biological function","volume":"404","author":"Michan","year":"2007","journal-title":"Biochem. J."},{"key":"2024061318305103700_JCS226274C15","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1016\/j.jhep.2006.05.007","article-title":"PD-L1 is induced in hepatocytes by viral infection and by interferon-alpha and -gamma and mediates T cell apoptosis","volume":"45","author":"M\u00fchlbauer","year":"2006","journal-title":"J. Hepatol."},{"key":"2024061318305103700_JCS226274C16","doi-asserted-by":"publisher","first-page":"e137","DOI":"10.1038\/cti.2017.12","article-title":"The role of PD-1 in regulation of macrophage apoptosis and its subversion by Leishmania donovani","volume":"6","author":"Roy","year":"2017","journal-title":"Clin. Transl. Immunol."},{"key":"2024061318305103700_JCS226274C17","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1111\/j.1462-5822.2006.00769.x","article-title":"Leishmania promastigotes activate PI3K\/Akt signalling to confer host cell resistance to apoptosis","volume":"9","author":"Ruhland","year":"2007","journal-title":"Cell. Microbiol."},{"key":"2024061318305103700_JCS226274C18","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1002\/bies.20799","article-title":"SIRT1 longevity factor suppresses NF-kappaB -driven immune responses: regulation of aging via NF-kappaB acetylation?","volume":"30","author":"Salminen","year":"2008","journal-title":"BioEssays"},{"key":"2024061318305103700_JCS226274C19","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1002\/ijc.25397","article-title":"PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients","volume":"128","author":"Shi","year":"2011","journal-title":"Int. J. Cancer"},{"key":"2024061318305103700_JCS226274C20","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1074\/jbc.M113.496323","article-title":"Leishmania donovani prevents oxidative burst-mediated apoptosis of host macrophages through selective induction of suppressors of cytokine signaling (SOCS) proteins","volume":"289","author":"Srivastav","year":"2014","journal-title":"J. Biol. Chem."},{"key":"2024061318305103700_JCS226274C21","doi-asserted-by":"publisher","first-page":"1938","DOI":"10.1016\/j.bbamcr.2011.06.002","article-title":"FoxO transcription factors; Regulation by AKT and 14-3-3 proteins","volume":"1813","author":"Tzivion","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"2024061318305103700_JCS226274C22","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1007\/s10495-013-0833-7","article-title":"SIRT1 inhibits TNF-alpha-induced apoptosis of vascular adventitial fibroblasts partly through the deacetylation of FoxO1","volume":"18","author":"Wang","year":"2013","journal-title":"Apoptosis"},{"key":"2024061318305103700_JCS226274C23","doi-asserted-by":"publisher","first-page":"925350","DOI":"10.1155\/2014\/925350","article-title":"FOXO transcription factors: their clinical significance and regulation","volume":"2014","author":"Wang","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"2024061318305103700_JCS226274C24","doi-asserted-by":"publisher","first-page":"693","DOI":"10.2174\/157016112803520756","article-title":"SIRT1 - an anti-inflammatory pathway at the crossroads between metabolic disease and atherosclerosis","volume":"10","author":"Winnik","year":"2012","journal-title":"Curr. Vasc. Pharmacol."},{"key":"2024061318305103700_JCS226274C25","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1593\/neo.81358","article-title":"Acetylation of FoxO1 activates Bim expression to induce apoptosis in response to histone deacetylase inhibitor depsipeptide treatment","volume":"11","author":"Yang","year":"2009","journal-title":"Neoplasia"},{"key":"2024061318305103700_JCS226274C26","doi-asserted-by":"publisher","first-page":"e46364","DOI":"10.1371\/journal.pone.0046364","article-title":"SIRT1 activators suppress inflammatory responses through promotion of p65 deacetylation and inhibition of NF-kappaB activity","volume":"7","author":"Yang","year":"2012","journal-title":"PLoS ONE"},{"key":"2024061318305103700_JCS226274C27","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1128\/MCB.00705-08","article-title":"SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes","volume":"29","author":"Yoshizaki","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"2024061318305103700_JCS226274C28","doi-asserted-by":"publisher","first-page":"1978","DOI":"10.1016\/j.bbamcr.2011.03.010","article-title":"Akt, FoxO and regulation of apoptosis","volume":"1813","author":"Zhang","year":"2011","journal-title":"Biochim. Biophys. Acta"}],"container-title":["Journal of Cell Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/jcs.226274","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/jcs\/article-pdf\/doi\/10.1242\/jcs.226274\/3507989\/jcs226274.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/jcs\/article-pdf\/doi\/10.1242\/jcs.226274\/2059650\/jcs_226274v1.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/jcs\/article-pdf\/doi\/10.1242\/jcs.226274\/3507989\/jcs226274.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T19:53:19Z","timestamp":1718308399000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/jcs\/article\/132\/9\/jcs226274\/121\/Crosstalk-of-PD-1-signaling-with-the-SIRT1-FOXO-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,1]]},"references-count":28,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2019,5,1]]}},"URL":"https:\/\/doi.org\/10.1242\/jcs.226274","relation":{},"ISSN":["1477-9137","0021-9533"],"issn-type":[{"value":"1477-9137","type":"electronic"},{"value":"0021-9533","type":"print"}],"subject":[],"published":{"date-parts":[[2019,5,1]]},"article-number":"jcs226274"}}