{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:30:44Z","timestamp":1787009444938,"version":"build-2736575974"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T00:00:00Z","timestamp":1730246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"publisher","award":["AI130126"],"award-info":[{"award-number":["AI130126"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Federation of African Immunological Societies"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Co-inhibitory receptors (immune checkpoints) regulate activated immune cells. Their expression on T cells can limit host defense. We hypothesized that chronic Leishmania donovani infection in patients with visceral leishmaniasis (VL) leads to expression of co-inhibitory receptors that could be markers of treatment response and clinical outcome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>A prospective cohort of 21 subjects with VL (7 with HIV coinfection) and 10 controls was established to measure T-cell expression of co-inhibitory receptors (PD-1, Tim-3, LAG-3, CTLA-4, and TIGIT) by flow cytometry in discarded remnants of diagnostic splenic or bone marrow aspirates and peripheral blood collected before and after treatment. Plasma levels of soluble co-inhibitory proteins (sPD-1, sTim-3, sLAG-3, and sCTLA-4) and selected cytokines were determined by immunoassay.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Expression of co-inhibitory receptors in peripheral blood T cells generally reflected findings in spleen and bone marrow aspirates. PD-1 and Tim-3 were upregulated in CD4+ T cells in HIV-negative and HIV-positive subjects with VL compared to controls. CD8+ T cells from HIV-negative subjects with VL displayed a similar pattern. Plasma levels of sPD-1 and sTim-3 were also greater in VL patients than controls. CD8+ and CD4+ T cells coexpressing PD-1 and Tim-3 showed considerable decline with treatment. Mortality in HIV-negative VL patients was associated with increased CD8+ T cells coexpressing Tim-3 and PD-1, triple-positive CD4+ and CD8+ T cells (PD-1+Tim-3+LAG-3+), and elevated sLAG3.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Tim-3 and PD-1 expression on CD4+ and CD8+ T cells, and increased plasma sLAG-3, were markers of treatment response and clinical outcome in patients with VL.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ofid\/ofae649","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T16:15:45Z","timestamp":1730132145000},"source":"Crossref","is-referenced-by-count":2,"title":["T-cell and Soluble Co-inhibitory Receptor Expression in Patients With Visceral Leishmaniasis Are Markers of Treatment Response and Clinical Outcome"],"prefix":"10.1093","volume":"11","author":[{"given":"Muluneh","family":"Ademe","sequence":"first","affiliation":[{"name":"Department of Microbiology, Immunology & Parasitology, College of Health Sciences, Addis Ababa University , Addis Ababa ,","place":["Ethiopia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaneth","family":"Osorio","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch , Galveston, Texas ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helina","family":"Fikre","sequence":"additional","affiliation":[{"name":"Leishmaniasis Research and Treatment Center, University of Gondar , Gondar ,","place":["Ethiopia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desalegn","family":"Adane","sequence":"additional","affiliation":[{"name":"Leishmaniasis Research and Treatment Center, University of Gondar , Gondar ,","place":["Ethiopia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadele","family":"Mulaw","sequence":"additional","affiliation":[{"name":"Leishmaniasis Research and Treatment Center, University of Gondar , Gondar ,","place":["Ethiopia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno L","family":"Travi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch , Galveston, Texas ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rawliegh","family":"Howe","sequence":"additional","affiliation":[{"name":"Aramuer Hansen Research Institute (AHRI) , Addis Ababa ,","place":["Ethiopia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asrat","family":"Hailu","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology & Parasitology, College of Health Sciences, Addis Ababa University , Addis Ababa ,","place":["Ethiopia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamrat","family":"Abebe","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology & Parasitology, College of Health Sciences, Addis Ababa University , Addis Ababa ,","place":["Ethiopia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7320-7406","authenticated-orcid":false,"given":"Peter C","family":"Melby","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch , Galveston, Texas ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,10,30]]},"reference":[{"key":"2024112610465985900_ofae649-B1","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S0140-6736(18)31204-2","article-title":"Leishmaniasis","volume":"392","author":"Burza","year":"2018","journal-title":"Lancet"},{"key":"2024112610465985900_ofae649-B2","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1038\/nrmicro1748","article-title":"Visceral leishmaniasis: what are the needs for diagnosis, treatment and control?","volume":"5","author":"Chappuis","year":"2007","journal-title":"Nat Rev Microbiol"},{"key":"2024112610465985900_ofae649-B3","doi-asserted-by":"crossref","first-page":"251","DOI":"10.3389\/fimmu.2012.00251","article-title":"Immunobiology of visceral leishmaniasis","volume":"3","author":"Kumar","year":"2012","journal-title":"Front Immunol"},{"key":"2024112610465985900_ofae649-B4","doi-asserted-by":"crossref","first-page":"e2914","DOI":"10.1371\/journal.pntd.0002914","article-title":"Immune regulation during chronic visceral leishmaniasis","volume":"8","author":"Faleiro","year":"2014","journal-title":"PLoS Negl Trop Dis"},{"key":"2024112610465985900_ofae649-B5","doi-asserted-by":"crossref","first-page":"785153","DOI":"10.3389\/fgene.2021.785153","article-title":"Current progress and future perspectives of immune checkpoint in cancer and infectious diseases","volume":"12","author":"Cai","year":"2021","journal-title":"Front Genet"},{"key":"2024112610465985900_ofae649-B6","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/nri.2017.112","article-title":"Immune checkpoint blockade in infectious diseases","volume":"18","author":"Wykes","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"2024112610465985900_ofae649-B7","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/nri.2017.108","article-title":"The diverse functions of the PD1 inhibitory pathway","volume":"18","author":"Sharpe","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"2024112610465985900_ofae649-B8","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1126\/science.1202947","article-title":"Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4","volume":"332","author":"Qureshi","year":"2011","journal-title":"Science"},{"key":"2024112610465985900_ofae649-B9","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/imr.12519","article-title":"LAG3 (CD223) as a cancer immunotherapy target","volume":"276","author":"Andrews","year":"2017","journal-title":"Immunol Rev"},{"key":"2024112610465985900_ofae649-B10","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/imr.12520","article-title":"Tim-3 and its role in regulating anti-tumor immunity","volume":"276","author":"Das","year":"2017","journal-title":"Immunol Rev"},{"key":"2024112610465985900_ofae649-B11","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1111\/cei.13407","article-title":"TIGIT as an emerging immune checkpoint","volume":"200","author":"Harjunpaa","year":"2020","journal-title":"Clin Exp Immunol"},{"key":"2024112610465985900_ofae649-B12","doi-asserted-by":"crossref","first-page":"835711","DOI":"10.3389\/fimmu.2022.835711","article-title":"T lymphocyte exhaustion during human and experimental visceral leishmaniasis","volume":"13","author":"Costa-Madeira","year":"2022","journal-title":"Front Immunol"},{"key":"2024112610465985900_ofae649-B13","doi-asserted-by":"crossref","first-page":"620144","DOI":"10.3389\/fimmu.2021.620144","article-title":"Unraveling the role of immune checkpoints in leishmaniasis","volume":"12","author":"de Freitas E Silva","year":"2021","journal-title":"Front Immunol"},{"key":"2024112610465985900_ofae649-B14","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1093\/infdis\/jit401","article-title":"CD8 T cell exhaustion in human visceral leishmaniasis","volume":"209","author":"Gautam","year":"2014","journal-title":"J Infect Dis"},{"key":"2024112610465985900_ofae649-B15","doi-asserted-by":"crossref","first-page":"e0010544","DOI":"10.1371\/journal.pntd.0010544","article-title":"Impaired in vitro interferon-gamma production in patients with visceral leishmaniasis is improved by inhibition of PD1\/PDL-1 ligation","volume":"16","author":"Takele","year":"2022","journal-title":"PLoS Negl Trop Dis"},{"key":"2024112610465985900_ofae649-B16","doi-asserted-by":"crossref","first-page":"632667","DOI":"10.3389\/fimmu.2021.632667","article-title":"PD-1 Blockade modulates functional activities of exhausted-like T cell in patients with cutaneous leishmaniasis","volume":"12","author":"Garcia de Moura","year":"2021","journal-title":"Front Immunol"},{"key":"2024112610465985900_ofae649-B17","doi-asserted-by":"crossref","first-page":"5542","DOI":"10.4049\/jimmunol.1301810","article-title":"Programmed death 1-mediated T cell exhaustion during visceral leishmaniasis impairs phagocyte function","volume":"191","author":"Esch","year":"2013","journal-title":"J Immunol"},{"key":"2024112610465985900_ofae649-B18","doi-asserted-by":"crossref","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":"2024112610465985900_ofae649-B19","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/S1473-3099(16)30091-3","article-title":"Treatment of visceral leishmaniasis: pitfalls and stewardship","volume":"16","author":"Dorlo","year":"2016","journal-title":"Lancet Infect Dis"},{"key":"2024112610465985900_ofae649-B20","doi-asserted-by":"crossref","first-page":"36","DOI":"10.3390\/tropicalmed8010036","article-title":"Hematological and clinical features associated with initial poor treatment outcomes in visceral leishmaniasis patients with and without HIV coinfection in Gondar, Northwest Ethiopia","volume":"8","author":"Ademe","year":"2023","journal-title":"Trop Med Infect Dis"},{"key":"2024112610465985900_ofae649-B21","author":"Federal Ministry of Health","year":"2013"},{"key":"2024112610465985900_ofae649-B22","volume-title":"Control of the leishmaniases: WHO TRS N\u00b0949","author":"World Health Organization","year":"2010"},{"key":"2024112610465985900_ofae649-B23","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/s40425-018-0449-0","article-title":"Soluble immune checkpoints in cancer: production, function and biological significance","volume":"6","author":"Gu","year":"2018","journal-title":"J Immunother Cancer"},{"key":"2024112610465985900_ofae649-B24","doi-asserted-by":"crossref","first-page":"e00019\u201318","DOI":"10.1128\/IAI.00019-18","article-title":"PDL-1 Blockade prevents T cell exhaustion, inhibits autophagy, and promotes clearance of leishmania donovani","volume":"86","author":"Habib","year":"2018","journal-title":"Infect Immun"},{"key":"2024112610465985900_ofae649-B25","doi-asserted-by":"crossref","first-page":"e12669","DOI":"10.1111\/pim.12669","article-title":"A molecular signature for CD8(+) T cells from visceral leishmaniasis patients","volume":"41","author":"Singh","year":"2019","journal-title":"Parasite Immunol"},{"key":"2024112610465985900_ofae649-B26","doi-asserted-by":"crossref","first-page":"e0330921","DOI":"10.1128\/mbio.03309-21","article-title":"Leishmania donovani impedes antileishmanial immunity by suppressing dendritic cells via the TIM-3 receptor","volume":"13","author":"Akhtar","year":"2022","journal-title":"mBio"},{"key":"2024112610465985900_ofae649-B27","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/s41586-018-0206-z","article-title":"Induction and transcriptional regulation of the co-inhibitory gene module in T cells","volume":"558","author":"Chihara","year":"2018","journal-title":"Nature"},{"key":"2024112610465985900_ofae649-B28","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.ajpath.2014.11.003","article-title":"LAG3 expression in active Mycobacterium tuberculosis infections","volume":"185","author":"Phillips","year":"2015","journal-title":"Am J Pathol"},{"key":"2024112610465985900_ofae649-B29","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1158\/2326-6066.CIR-20-0736","article-title":"Systemic immune dysfunction in cancer patients driven by IL6 induction of LAG3 in peripheral CD8+ T cells","volume":"10","author":"Somasundaram","year":"2022","journal-title":"Cancer Immunol Res"},{"key":"2024112610465985900_ofae649-B30","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1093\/cid\/cix607","article-title":"The risk and predictors of visceral leishmaniasis relapse in human immunodeficiency virus-coinfected patients in Ethiopia: a retrospective cohort study","volume":"65","author":"Abongomera","year":"2017","journal-title":"Clin Infect Dis"},{"key":"2024112610465985900_ofae649-B31","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1186\/s40249-018-0491-7","article-title":"Treatment outcomes of visceral leishmaniasis in Ethiopia from 2001 to 2017: a systematic review and meta-analysis","volume":"7","author":"Gebreyohannes","year":"2018","journal-title":"Infect Dis Poverty"},{"key":"2024112610465985900_ofae649-B32","doi-asserted-by":"crossref","first-page":"e0009713","DOI":"10.1371\/journal.pntd.0009713","article-title":"Efficacy and safety of a combined treatment of sodium stibogluconate at 20 mg\/kg\/day with upper maximum daily dose limit of 850\u2005mg and paromomycin 15\u2005mg\/kg\/day in HIV negative visceral leishmaniasis patients. A retrospective study, northwest Ethiopia","volume":"15","author":"Tamiru","year":"2021","journal-title":"PLoS Negl Trop Dis"},{"key":"2024112610465985900_ofae649-B33","doi-asserted-by":"crossref","first-page":"e0008319","DOI":"10.1371\/journal.pntd.0008319","article-title":"Prognostic factors for mortality among patients with visceral leishmaniasis in east Africa: systematic review and meta-analysis","volume":"14","author":"Abongomera","year":"2020","journal-title":"PLoS Negl Trop Dis"},{"key":"2024112610465985900_ofae649-B34","doi-asserted-by":"crossref","first-page":"e3374","DOI":"10.1371\/journal.pntd.0003374","article-title":"Prognostic factors and scoring system for death from visceral leishmaniasis: an historical cohort study in Brazil","volume":"8","author":"Coura-Vital","year":"2014","journal-title":"PLoS Negl Trop Dis"},{"key":"2024112610465985900_ofae649-B35","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.clim.2005.06.015","article-title":"T cell subset and cytokine profiles in human visceral leishmaniasis during active and asymptomatic or sub-clinical infection with Leishmania donovani","volume":"117","author":"Hailu","year":"2005","journal-title":"Clin Immunol"},{"key":"2024112610465985900_ofae649-B36","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.it.2007.07.004","article-title":"Interleukin-10 and the pathogenesis of human visceral leishmaniasis","volume":"28","author":"Nylen","year":"2007","journal-title":"Trends Immunol"}],"container-title":["Open Forum Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ofid\/advance-article-pdf\/doi\/10.1093\/ofid\/ofae649\/60242306\/ofae649.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ofid\/article-pdf\/11\/11\/ofae649\/60793656\/ofae649.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ofid\/article-pdf\/11\/11\/ofae649\/60793656\/ofae649.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T05:47:56Z","timestamp":1732600076000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ofid\/article\/doi\/10.1093\/ofid\/ofae649\/7852787"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,30]]},"references-count":36,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2024,10,30]]}},"URL":"https:\/\/doi.org\/10.1093\/ofid\/ofae649","relation":{},"ISSN":["2328-8957"],"issn-type":[{"value":"2328-8957","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,11]]},"published":{"date-parts":[[2024,10,30]]},"article-number":"ofae649"}}