{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T18:24:04Z","timestamp":1771611844678,"version":"3.50.1"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2011,12,1]],"date-time":"2011-12-01T00:00:00Z","timestamp":1322697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>In visceral leishmaniasis, Th1 types of immune responses correlate with recovery from and resistance to disease, and resolution of infection results in lifelong immunity against the disease. Leishmanial Ags that elicit proliferative and cytokine responses in PBMCs from cured\/exposed\/Leishmania patients have been characterized through proteomic approaches, and elongation factor-2 is identified as one of the potent immunostimulatory proteins. In this study, we report the cloning and expression of Leishmania donovani elongation factor-2 protein (LelF-2) and its immunogenicity in PBMCs of cured\/exposed Leishmania-infected patients and hamsters (Mesocricetus auratus). Leishmania-infected cured\/exposed patients and hamsters exhibited significantly higher proliferative responses to recombinant Lelf-2 (rLelF-2) than those with L. donovani-infected hosts. The soluble L. donovani Ag stimulated PBMCs of cured\/exposed and Leishmania patients to produce a mixed Thl\/Th2-type cytokine profile, whereas rLelF-2 stimulated the production of IFN-\u03b3, IL-12, and TNF-\u03b1 but not IL-4 or IL-10. Further, rLelF-2 downregulated LPS-induced IL-10 as well as soluble L. donovani Ag-induced IL-4 production by Leishmania patient PBMCs. The immunogenicity of rLelF-2 was also checked in hamsters in which rLelF-2 generates strong IL-12\u2013 and IFN-\u03b3\u2013mediated Th1 immune response. This was further supported by a remarkable increase in IgG2 Ab level. We further demonstrated that rLelF-2 was able to provide considerable protection (\u223c65%) to hamsters against L. donovani challenge. The efficacy was supported by the increased inducible NO synthase mRNA transcript and Th1-type cytokines IFN-\u03b3, IL-12, and TNF-\u03b1 and downregulation of IL-4, IL-10, and TGF-\u03b2. Hence, it is inferred that rLelF-2 elicits a Th1 type of immune response exclusively and confers considerable protection against experimental visceral leishmaniasis.<\/jats:p>","DOI":"10.4049\/jimmunol.1102081","type":"journal-article","created":{"date-parts":[[2011,11,12]],"date-time":"2011-11-12T08:25:37Z","timestamp":1321086337000},"page":"6417-6427","source":"Crossref","is-referenced-by-count":72,"title":["Elongation Factor-2, a Th1 Stimulatory Protein of <i>Leishmania donovani<\/i>, Generates Strong IFN-\u03b3 and IL-12 Response in Cured <i>Leishmania<\/i>-Infected Patients\/Hamsters and Protects Hamsters against <i>Leishmania<\/i> Challenge"],"prefix":"10.1093","volume":"187","author":[{"given":"Pramod K","family":"Kushawaha","sequence":"first","affiliation":[{"name":"Division of Parasitology, Central Drug Research Institute , Lucknow 226 001 ,","place":["India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reema","family":"Gupta","sequence":"additional","affiliation":[{"name":"Division of Parasitology, Central Drug Research Institute , Lucknow 226 001 ,","place":["India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shyam","family":"Sundar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Institute of Medical Sciences, Benaras Hindu University , Varanasi 221 005 ,","place":["India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amogh A","family":"Sahasrabuddhe","sequence":"additional","affiliation":[{"name":"Division of Molecular and Structural Biology, Central Drug Research Institute , Lucknow 226 001 ,","place":["India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anuradha","family":"Dube","sequence":"additional","affiliation":[{"name":"Division of Parasitology, Central Drug Research Institute , Lucknow 226 001 ,","place":["India"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2011,12,15]]},"reference":[{"key":"2025032410513877600_r1","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1016\/S0140-6736(98)10178-2","article-title":"Leishmaniasis","volume":"354","author":"Herwaldt","year":"1999","journal-title":"Lancet"},{"key":"2025032410513877600_r2","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/S1473-3099(02)00347-X","article-title":"Visceral leishmaniasis: current status of control, diagnosis, and treatment, and a proposed research and development agenda","volume":"2","author":"Guerin","year":"2002","journal-title":"Lancet Infect. Dis."},{"key":"2025032410513877600_r3","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1111\/j.1365-3156.2006.01647.x","article-title":"Serious underreporting of visceral leishmaniasis through passive case reporting in Bihar, India","volume":"11","author":"Singh","year":"2006","journal-title":"Trop. Med. Int. Health"},{"key":"2025032410513877600_r4","doi-asserted-by":"crossref","first-page":"9","DOI":"10.4269\/ajtmh.2010.09-0235","article-title":"Estimation of under-reporting of visceral leishmaniasis cases in Bihar, India","volume":"82","author":"Singh","year":"2010","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"2025032410513877600_r5","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.cimid.2004.03.004","article-title":"Leishmaniasis: current situation and new perspectives","volume":"27","author":"Desjeux","year":"2004","journal-title":"Comp. Immunol. Microbiol. Infect. Dis."},{"key":"2025032410513877600_r6","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1128\/CMR.14.2.229-243.2001","article-title":"Leishmaniasis: current status of vaccine development","volume":"14","author":"Handman","year":"2001","journal-title":"Clin. Microbiol. Rev."},{"key":"2025032410513877600_r7","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1128\/iai.42.2.702-707.1983","article-title":"Cell-mediated immune response in Indian kala-azar and post-kala-azar dermal leishmaniasis","volume":"42","author":"Haldar","year":"1983","journal-title":"Infect. Immun."},{"key":"2025032410513877600_r8","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1172\/JCI116372","article-title":"In vivo cytokine profiles in patients with kala-azar. Marked elevation of both interleukin-10 and interferon-gamma","volume":"91","author":"Karp","year":"1993","journal-title":"J. Clin. Invest."},{"key":"2025032410513877600_r9","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1111\/j.1365-3083.2005.01686.x","article-title":"Immune response in human visceral leishmaniasis: analysis of the correlation between innate immunity cytokine profile and disease outcome","volume":"62","author":"Peruhype-Magalh\u00e3es","year":"2005","journal-title":"Scand. J. Immunol."},{"key":"2025032410513877600_r10","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1128\/iai.61.3.1069-1073.1993","article-title":"Leishmania donovani-reactive Th1- and Th2-like T-cell clones from individuals who have recovered from visceral leishmaniasis","volume":"61","author":"Kemp","year":"1993","journal-title":"Infect. Immun."},{"key":"2025032410513877600_r11","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1084\/jem.185.5.867","article-title":"Behavior of visceral Leishmania donovani in an experimentally induced T helper cell 2 (Th2)-associated response model","volume":"185","author":"Murray","year":"1997","journal-title":"J. Exp. Med."},{"key":"2025032410513877600_r12","doi-asserted-by":"crossref","first-page":"6544","DOI":"10.1016\/j.vaccine.2007.05.042","article-title":"Leishmanial antigens in liposomes promote protective immunity and provide immunotherapy against visceral leishmaniasis via polarized Th1 response","volume":"25","author":"Bhowmick","year":"2007","journal-title":"Vaccine"},{"key":"2025032410513877600_r13","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/0952-7915(93)90033-O","article-title":"T-cell and cytokine responses in leishmaniasis","volume":"5","author":"Reed","year":"1993","journal-title":"Curr. Opin. Immunol."},{"key":"2025032410513877600_r14","doi-asserted-by":"crossref","first-page":"6171","DOI":"10.4049\/jimmunol.161.11.6171","article-title":"LeIF: a recombinant Leishmania protein that induces an IL-12-mediated Th1 cytokine profile","volume":"161","author":"Skeiky","year":"1998","journal-title":"J. Immunol."},{"key":"2025032410513877600_r15","doi-asserted-by":"crossref","first-page":"4215","DOI":"10.1128\/IAI.70.8.4215-4225.2002","article-title":"Immunization with a polyprotein vaccine consisting of the T-Cell antigens thiol-specific antioxidant, Leishmania major stress-inducible protein 1, and Leishmania elongation initiation factor protects against leishmaniasis","volume":"70","author":"Coler","year":"2002","journal-title":"Infect. 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Immunol."},{"key":"2025032410513877600_r19","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1002\/pmic.200600725","article-title":"Proteomic approach for identification and characterization of novel immunostimulatory proteins from soluble antigens of Leishmania donovani promastigotes","volume":"7","author":"Gupta","year":"2007","journal-title":"Proteomics"},{"key":"2025032410513877600_r20","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1007\/s00436-005-1339-1","article-title":"Refractoriness to the treatment of sodium stibogluconate in Indian kala-azar field isolates persist in in vitro and in vivo experimental models","volume":"96","author":"Dube","year":"2005","journal-title":"Parasitol. Res."},{"key":"2025032410513877600_r21","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0021-9258(19)52451-6","article-title":"Protein measurement with the Folin phenol reagent","volume":"193","author":"Lowry","year":"1951","journal-title":"J. Biol. Chem."},{"key":"2025032410513877600_r22","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1002\/eji.1830240328","article-title":"Production of nitric oxide and superoxide by activated macrophages and killing of Leishmania major","volume":"24","author":"Assreuy","year":"1994","journal-title":"Eur. J. Immunol."},{"key":"2025032410513877600_r23","doi-asserted-by":"crossref","first-page":"4350","DOI":"10.1073\/pnas.76.9.4350","article-title":"Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications","volume":"76","author":"Towbin","year":"1979","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032410513877600_r24","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.4049\/jimmunol.141.7.2407","article-title":"Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production","volume":"141","author":"Ding","year":"1988","journal-title":"J. Immunol."},{"key":"2025032410513877600_r25","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1128\/IAI.66.5.2135-2142.1998","article-title":"Cloning of Syrian hamster (Mesocricetus auratus) cytokine cDNAs and analysis of cytokine mRNA expression in experimental visceral leishmaniasis","volume":"66","author":"Melby","year":"1998","journal-title":"Infect. Immun."},{"key":"2025032410513877600_r26","doi-asserted-by":"crossref","first-page":"470","DOI":"10.4049\/jimmunol.0900265","article-title":"Immunization with the DNA-encoding N-terminal domain of proteophosphoglycan of Leishmania donovani generates Th1-type immunoprotective response against experimental visceral leishmaniasis","volume":"183","author":"Samant","year":"2009","journal-title":"J. Immunol."},{"key":"2025032410513877600_r27","doi-asserted-by":"crossref","first-page":"5700","DOI":"10.1016\/j.vaccine.2008.08.021","article-title":"Th1-stimulatory polyproteins of soluble Leishmania donovani promastigotes ranging from 89.9 to 97.1kDa offers long-lasting protection against experimental visceral leishmaniasis","volume":"26","author":"Kumari","year":"2008","journal-title":"Vaccine"},{"key":"2025032410513877600_r28","doi-asserted-by":"crossref","first-page":"49003","DOI":"10.1074\/jbc.M407958200","article-title":"Leishmania major elongation factor 1B complex has trypanothione S-transferase and peroxidase activity","volume":"279","author":"Vickers","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2025032410513877600_r29","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/S0006-291X(03)00216-X","article-title":"Molecular cloning, biochemical and structural analysis of elongation factor-1 alpha from Leishmania donovani: comparison with the mammalian homologue","volume":"302","author":"Nandan","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2025032410513877600_r30","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.bbrc.2007.03.077","article-title":"Molecular architecture of leishmania EF-1alpha reveals a novel site that may modulate protein translation: a possible target for drug development","volume":"356","author":"Lopez","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2025032410513877600_r31","doi-asserted-by":"crossref","first-page":"4813","DOI":"10.1016\/j.vaccine.2008.06.102","article-title":"Induction of Th1-type cellular responses in cured\/exposed Leishmania-infected patients and hamsters against polyproteins of soluble Leishmania donovani promastigotes ranging from 89.9 to 97.1 kDa","volume":"26","author":"Kumari","year":"2008","journal-title":"Vaccine"},{"key":"2025032410513877600_r32","doi-asserted-by":"crossref","first-page":"3009","DOI":"10.1002\/eji.1830211216","article-title":"Resistance to Leishmania major infection correlates with the induction of nitric oxide synthase in murine macrophages","volume":"21","author":"Liew","year":"1991","journal-title":"Eur. J. Immunol."},{"key":"2025032410513877600_r33","doi-asserted-by":"crossref","first-page":"266","DOI":"10.4049\/jimmunol.143.1.266","article-title":"Administration of monoclonal anti-IFN-gamma antibodies in vivo abrogates natural resistance of C3H\/HeN mice to infection with Leishmania major","volume":"143","author":"Belosevic","year":"1989","journal-title":"J. Immunol."},{"key":"2025032410513877600_r34","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.4049\/jimmunol.147.5.1653","article-title":"Reconstitution of Leishmania immunity in severe combined immunodeficient mice using Th1- and Th2-like cell lines","volume":"147","author":"Holaday","year":"1991","journal-title":"J. Immunol."},{"key":"2025032410513877600_r35","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1146\/annurev.immunol.15.1.323","article-title":"Nitric oxide and macrophage function","volume":"15","author":"MacMicking","year":"1997","journal-title":"Annu. Rev. Immunol."},{"key":"2025032410513877600_r36","doi-asserted-by":"crossref","first-page":"742","DOI":"10.4049\/jimmunol.146.2.742","article-title":"Characterization of a membrane antigen of Leishmania amazonensis that stimulates human immune responses","volume":"146","author":"Burns","year":"1991","journal-title":"J. Immunol."},{"key":"2025032410513877600_r37","doi-asserted-by":"crossref","first-page":"3575","DOI":"10.4049\/jimmunol.147.10.3575","article-title":"Human T cell responses to gp63, a surface antigen of Leishmania","volume":"147","author":"Russo","year":"1991","journal-title":"J. Immunol."},{"key":"2025032410513877600_r38","doi-asserted-by":"crossref","first-page":"123","DOI":"10.4269\/ajtmh.1992.46.123","article-title":"Leishmania chagasi antigens recognized in cured visceral leishmaniasis and asymptomatic infection","volume":"46","author":"White","year":"1992","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"2025032410513877600_r39","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1046\/j.1365-3083.2000.00724.x","article-title":"Distinct innate and acquired immune responses to Leishmania in putative susceptible and resistant human populations endemically exposed to L. (Viannia) panamensis infection","volume":"51","author":"Bosque","year":"2000","journal-title":"Scand. J. Immunol."},{"key":"2025032410513877600_r40","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1590\/S0074-02761999000300015","article-title":"T cell response of asymptomatic Leishmania chagasi infected subjects to recombinant leishmania antigens","volume":"94","author":"Costa","year":"1999","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"2025032410513877600_r41","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1002\/eji.1830200528","article-title":"Tumor necrosis factor-alpha in combination with interferon-gamma, but not with interleukin 4 activates murine macrophages for elimination of Leishmania major amastigotes","volume":"20","author":"Bogdan","year":"1990","journal-title":"Eur. J. Immunol."},{"key":"2025032410513877600_r42","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1002\/eji.1830190712","article-title":"Macrophage activation by interferon-gamma from host-protective T cells is inhibited by interleukin (IL)3 and IL4 produced by disease-promoting T cells in leishmaniasis","volume":"19","author":"Liew","year":"1989","journal-title":"Eur. J. Immunol."},{"key":"2025032410513877600_r43","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1084\/jem.170.6.2097","article-title":"Tumor necrosis factor plays a protective role in experimental murine cutaneous leishmaniasis","volume":"170","author":"Titus","year":"1989","journal-title":"J. Exp. Med."},{"key":"2025032410513877600_r44","doi-asserted-by":"crossref","first-page":"6853","DOI":"10.4049\/jimmunol.151.12.6853","article-title":"Predominant role of tumor necrosis factor-alpha in human monocyte IL-10 synthesis","volume":"151","author":"Wanidworanun","year":"1993","journal-title":"J. Immunol."},{"key":"2025032410513877600_r45","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1084\/jem.177.2.523","article-title":"Interferon gamma inhibits interleukin 10 production by monocytes","volume":"177","author":"Chomarat","year":"1993","journal-title":"J. Exp. Med."},{"key":"2025032410513877600_r46","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/0167-5699(93)90230-I","article-title":"Interleukin-12 and its role in the generation of TH1 cells","volume":"14","author":"Trinchieri","year":"1993","journal-title":"Immunol. Today"},{"key":"2025032410513877600_r47","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1084\/jem.170.3.827","article-title":"Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes","volume":"170","author":"Kobayashi","year":"1989","journal-title":"J. Exp. Med."},{"key":"2025032410513877600_r48","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1084\/jem.177.4.1199","article-title":"Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells","volume":"177","author":"Manetti","year":"1993","journal-title":"J. Exp. 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