{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:49:27Z","timestamp":1760233767195,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T00:00:00Z","timestamp":1613606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008662","name":"Joachim Herz Stiftung","doi-asserted-by":"publisher","award":["Graduate School of Infection Biology at the Bernhard Nocht Institute for Tropical Medicine"],"award-info":[{"award-number":["Graduate School of Infection Biology at the Bernhard Nocht Institute for Tropical Medicine"]}],"id":[{"id":"10.13039\/100008662","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009139","name":"Deutsches Zentrum f\u00fcr Infektionsforschung","doi-asserted-by":"publisher","award":["TI 07.003 - FP2016: MD Programm"],"award-info":[{"award-number":["TI 07.003 - FP2016: MD Programm"]}],"id":[{"id":"10.13039\/100009139","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>An immunostimulatory glycolipid molecule from the intestinal protozoan parasite Entamoeba histolytica (Eh) and its synthetic analogs derived from its phosphatidylinositol-b-anchor (EhPIb) previously showed considerable immunotherapeutic effects against Leishmania major infection in vitro and in vivo. Here, we describe a high content screening assay, based on primary murine macrophages. Parasites detection is based on a 90 kDA heat shock protein-specific staining, enabling the detection of several Leishmania species. We validated the assay using L. major, L. braziliensis, L. donovani, and L. infantum as well as investigated the anti-leishmanial activity of six immunostimulatory EhPIb-compounds (Eh-1 to Eh-6). Macrophages infected with dermotropic species were more sensitive towards treatment with the compounds as their viability showed a stronger reduction compared to macrophages infected with viscerotropic species. Most compounds caused a significant reduction of the infection rates and the parasite burdens depending on the infecting species. Only compound Eh-6 was found to have activity against all Leishmania species. Considering the challenges in anti-leishmanial drug discovery, we developed a multi-species screening assay capable of utilizing non-recombinant parasite strains, and demonstrated its usefulness by screening macrophage-targeting EhPIb-compounds showing their potential for the treatment of cutaneous and visceral leishmaniasis.<\/jats:p>","DOI":"10.3390\/microorganisms9020422","type":"journal-article","created":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T20:56:21Z","timestamp":1613681781000},"page":"422","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["High Content Analysis of Macrophage-Targeting EhPIb-Compounds against Cutaneous and Visceral Leishmania Species"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1112-7608","authenticated-orcid":false,"given":"Helena","family":"Fehling","sequence":"first","affiliation":[{"name":"Department of Molecular Parasitology and Immunology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanno","family":"Niss","sequence":"additional","affiliation":[{"name":"Department of Molecular Parasitology and Immunology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annika","family":"Bea","sequence":"additional","affiliation":[{"name":"Department of Molecular Parasitology and Immunology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany"},{"name":"Leishmaniasis Group, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadine","family":"Kottmayr","sequence":"additional","affiliation":[{"name":"Department of Molecular Parasitology and Immunology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Brinker","sequence":"additional","affiliation":[{"name":"Leishmaniasis Group, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Hoenow","sequence":"additional","affiliation":[{"name":"Department of Molecular Parasitology and Immunology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"Sellau","sequence":"additional","affiliation":[{"name":"Department of Molecular Parasitology and Immunology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim-Wolf","family":"Gilberger","sequence":"additional","affiliation":[{"name":"Department of Molecular Parasitology and Immunology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany"},{"name":"Centre for Structural Systems Biology (CSSB), 22607 Hamburg, Germany"},{"name":"Biology Department, Faculty of Sciences, Universit\u00e4t Hamburg, 22609 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederic","family":"Ting","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Sciences, Universit\u00e4t Hamburg, 20146 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"Landschulze","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Sciences, Universit\u00e4t Hamburg, 20146 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris","family":"Meier","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Sciences, Universit\u00e4t Hamburg, 20146 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4377-8173","authenticated-orcid":false,"given":"Joachim","family":"Clos","sequence":"additional","affiliation":[{"name":"Leishmaniasis Group, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannelore","family":"Lotter","sequence":"additional","affiliation":[{"name":"Department of Molecular Parasitology and Immunology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,18]]},"reference":[{"key":"ref_1","unstructured":"WHO (2016). Leishmaniasis in high-burden countries: An epidemiological update based on data reported in 2014. Wkly. Epidemiol. Rec. Relev. Epidemiol. Hebd., 91, 285\u2013296."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Wertheim, H.F.L., Horby, P., and Woodall, J.P. (2012). Atlas of Human Infectious Diseases, John Wiley & Sons.","DOI":"10.1002\/9781444354690"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Caridha, D., Vesely, B., van Bocxlaer, K., Arana, B., Mowbray, C.E., Rafati, S., Uliana, S., Reguera, R., Kreishman-Deitrick, M., and Sciotti, R. (2019). Route map for the discovery and pre-clinical development of new drugs and treatments for cutaneous leishmaniasis. Int. J. Parasitol. Drugs Drug Resist.","DOI":"10.1016\/j.ijpddr.2019.06.003"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.pt.2003.09.008","article-title":"Leishmaniasis\u2014Current chemotherapy and recent advances in the search for novel drugs","volume":"19","author":"Croft","year":"2003","journal-title":"Trends Parasitol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"319","DOI":"10.2174\/1381612023396258","article-title":"Chemotherapy of leishmaniasis","volume":"8","author":"Croft","year":"2002","journal-title":"Curr. Pharm. Des."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Aulner, N., Danckaert, A., Rouault-Hardoin, E., Desrivot, J., Helynck, O., Commere, P.H., Munier-Lehmann, H., Spath, G.F., Shorte, S.L., and Milon, G. (2013). High content analysis of primary macrophages hosting proliferating Leishmania amastigotes: Application to anti-leishmanial drug discovery. PLoS Negl. Trop. Dis., 7.","DOI":"10.1371\/journal.pntd.0002154"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/s41598-018-36944-6","article-title":"Discovery of novel hit compounds with broad activity against visceral and cutaneous Leishmania species by comparative phenotypic screening","volume":"9","author":"Lamotte","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Siqueira-Neto, J.L., Moon, S., Jang, J., Yang, G., Lee, C., Moon, H.K., Chatelain, E., Genovesio, A., Cechetto, J., and Freitas-Junior, L.H. (2012). An image-based high-content screening assay for compounds targeting intracellular Leishmania donovani amastigotes in human macrophages. PLoS Negl. Trop. Dis., 6.","DOI":"10.1371\/journal.pntd.0001671"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Gomes-Alves, A.G., Maia, A.F., Cruz, T., Castro, H., and Tomas, A.M. (2018). Development of an automated image analysis protocol for quantification of intracellular forms of Leishmania spp.. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0201747"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Alcantara, L.M., Ferreira, T.C.S., Fontana, V., Chatelain, E., Moraes, C.B., and Freitas-Junior, L.H. (2020). A Multi-Species Phenotypic Screening Assay for Leishmaniasis Drug Discovery Shows That Active Compounds Display a High Degree of Species-Specificity. Molecules, 25.","DOI":"10.3390\/molecules25112551"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Lamotte, S., Spath, G.F., Rachidi, N., and Prina, E. (2017). The enemy within: Targeting host-parasite interaction for antileishmanial drug discovery. PLoS Negl. Trop. Dis., 11.","DOI":"10.1371\/journal.pntd.0005480"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"83","DOI":"10.3389\/fcimb.2012.00083","article-title":"The early interaction of Leishmania with macrophages and dendritic cells and its influence on the host immune response","volume":"2","author":"Liu","year":"2012","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Thacker, S.G., McWilliams, I.L., Bonnet, B., Halie, L., Beaucage, S., Rachuri, S., Dey, R., Duncan, R., Modabber, F., and Robinson, S. (2020). CpG ODN D35 improves the response to abbreviated low-dose pentavalent antimonial treatment in non-human primate model of cutaneous leishmaniasis. PLoS Negl. Trop. Dis., 14.","DOI":"10.1371\/journal.pntd.0008050"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4717","DOI":"10.4049\/jimmunol.170.9.4717","article-title":"CpG oligodeoxynucleotides protect normal and SIV-infected macaques from Leishmania infection","volume":"170","author":"Verthelyi","year":"2003","journal-title":"J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Miranda-Verastegui, C., Tulliano, G., Gyorkos, T.W., Calderon, W., Rahme, E., Ward, B., Cruz, M., Llanos-Cuentas, A., and Matlashewski, G. (2009). First-line therapy for human cutaneous leishmaniasis in Peru using the TLR7 agonist imiquimod in combination with pentavalent antimony. PLoS Negl. Trop. Dis., 3.","DOI":"10.1371\/journal.pntd.0000491"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2513","DOI":"10.1128\/AAC.47.8.2513-2517.2003","article-title":"Immunoenhancement combined with amphotericin B as treatment for experimental visceral leishmaniasis","volume":"47","author":"Murray","year":"2003","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1056\/NEJM199001043220104","article-title":"Treatment of visceral leishmaniasis with pentavalent antimony and interferon gamma","volume":"322","author":"Badaro","year":"1990","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1086\/314782","article-title":"Treatment of experimental leishmaniasis with the immunomodulators imiquimod and S-28463: Efficacy and mode of action","volume":"179","author":"Buates","year":"1999","journal-title":"J. Infect. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/S0140-6736(87)90116-4","article-title":"Immunotherapy versus chemotherapy in localised cutaneous leishmaniasis","volume":"1","author":"Convit","year":"1987","journal-title":"Lancet"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"El Hajj, R., Bou Youness, H., Lachaud, L., Bastien, P., Masquefa, C., Bonnet, P.A., El Hajj, H., and Khalifeh, I. (2018). EAPB0503: An Imiquimod analog with potent in vitro activity against cutaneous leishmaniasis caused by Leishmania major and Leishmania tropica. PLoS Negl. Trop. Dis., 12.","DOI":"10.1371\/journal.pntd.0006854"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lotter, H., Gonzalez-Roldan, N., Lindner, B., Winau, F., Isibasi, A., Moreno-Lafont, M., Ulmer, A.J., Holst, O., Tannich, E., and Jacobs, T. (2009). Natural killer T cells activated by a lipopeptidophosphoglycan from Entamoeba histolytica are critically important to control amebic liver abscess. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000434"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lotter, H., Helk, E., Bernin, H., Jacobs, T., Prehn, C., Adamski, J., Gonzalez-Roldan, N., Holst, O., and Tannich, E. (2013). Testosterone increases susceptibility to amebic liver abscess in mice and mediates inhibition of IFNgamma secretion in natural killer T cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0055694"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9472","DOI":"10.1038\/s41598-017-09894-8","article-title":"Synthetic analogs of an Entamoeba histolytica glycolipid designed to combat intracellular Leishmania infection","volume":"7","author":"Choy","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Fehling, H., Choy, S.L., Ting, F., Landschulze, D., Bernin, H., Lender, S.C., M\u00fchlenpfordt, M., Bifeld, E., Eick, J., and Marggraff, C. (2020). Anti-leishmanial effects of synthetic EhPIb analogs derived from the Entamoeba histolytica lipopeptidephosphoglycan. Antimicrob. Agents Chemother.","DOI":"10.1128\/AAC.00161-20"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Al-Jawabreh, A., Diezmann, S., Muller, M., Wirth, T., Schnur, L.F., Strelkova, M.V., Kovalenko, D.A., Razakov, S.A., Schwenkenbecher, J., and Kuhls, K. (2008). Identification of geographically distributed sub-populations of Leishmania (Leishmania) major by microsatellite analysis. BMC Evol. Biol., 8.","DOI":"10.1186\/1471-2148-8-183"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"272","DOI":"10.4269\/ajtmh.2005.73.272","article-title":"The sensitivity of clinical isolates of Leishmania from Peru and Nepal to miltefosine","volume":"73","author":"Yardley","year":"2005","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7365","DOI":"10.1128\/IAI.69.12.7365-7373.2001","article-title":"Virulence of Leishmania infantum is expressed as a clonal and dominant phenotype in experimental infections","volume":"69","author":"Garin","year":"2001","journal-title":"Infect. Immun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1016\/j.ijpara.2008.03.005","article-title":"Identification of a Leishmania infantum gene mediating resistance to miltefosine and SbIII","volume":"38","author":"Choudhury","year":"2008","journal-title":"Int. J. Parasitol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1086\/524042","article-title":"Clinical and parasite species risk factors for pentavalent antimonial treatment failure in cutaneous leishmaniasis in Peru","volume":"46","author":"Tulliano","year":"2008","journal-title":"Clin. Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/s00430-016-0460-3","article-title":"A versatile qPCR assay to quantify trypanosomatidic infections of host cells and tissues","volume":"205","author":"Bifeld","year":"2016","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/978-1-4939-9210-2_12","article-title":"Generation of Bone Marrow-Derived Macrophages for In Vitro Infection Experiments","volume":"1971","author":"Bifeld","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/jcp.1041250307","article-title":"Transformation of mouse bone marrow cells by transfection with a human oncogene related to c-myc is associated with the endogenous production of macrophage colony stimulating factor 1","volume":"125","author":"Sklar","year":"1985","journal-title":"J. Cell. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1111\/cmi.12057","article-title":"The Hsp90-Sti1 interaction is critical for Leishmania donovani proliferation in both life cycle stages","volume":"15","author":"Hombach","year":"2013","journal-title":"Cell. Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s12192-009-0160-7","article-title":"The co-chaperone SGT of Leishmania donovani is essential for the parasite\u2019s viability","volume":"15","author":"Ommen","year":"2010","journal-title":"Cell Stress Chaperones"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1177\/108705719900400206","article-title":"A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays","volume":"4","author":"Zhang","year":"1999","journal-title":"J. Biomol. Screen."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"300","DOI":"10.4269\/ajtmh.1983.32.300","article-title":"Thermosensitivity Patterns of Old vs. New World Cutaneous Strains of Leishmania Growing within Mouse Peritoneal Macrophages in Vitro","volume":"32","author":"Sacks","year":"1983","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/978-1-4939-9210-2_14","article-title":"In Vitro Infections of Macrophage-Like Cell Lines with Leishmania infantum for Drug Screening","volume":"1971","author":"Tavares","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/978-1-4939-9210-2_16","article-title":"Quantification of Leishmania Parasites in Murine Models of Visceral Infection","volume":"1971","author":"Tavares","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Alonso-Padilla, J., Cotillo, I., Presa, J.L., Cantizani, J., Pena, I., Bardera, A.I., Martin, J.J., and Rodriguez, A. (2015). Automated high-content assay for compounds selectively toxic to Trypanosoma cruzi in a myoblastic cell line. PLoS Negl. Trop. Dis., 9.","DOI":"10.1371\/journal.pntd.0003493"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.parint.2008.09.006","article-title":"Leishmania (Viannia) braziliensis transfectants overexpressing the miniexon gene lose virulence in vivo","volume":"58","author":"Antoniazi","year":"2009","journal-title":"Parasitol. Int."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.ijpddr.2013.11.004","article-title":"A novel marker, ARM58, confers antimony resistance to Leishmania spp.","volume":"4","author":"Nuhs","year":"2014","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1111\/j.1462-5822.2011.01593.x","article-title":"Quantitative proteome profiling informs on phenotypic traits that adapt Leishmania donovani for axenic and intracellular proliferation","volume":"13","author":"Pescher","year":"2011","journal-title":"Cell. Microbiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1111\/cmi.12440","article-title":"A touch of Zen: Post-translational regulation of the Leishmania stress response","volume":"17","author":"Drini","year":"2015","journal-title":"Cell. Microbiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s00430-016-0449-y","article-title":"The cytokine profile of human NKT cells and PBMCs is dependent on donor sex and stimulus","volume":"205","author":"Bernin","year":"2016","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Das, P., Lahiri, A., Lahiri, A., and Chakravortty, D. (2010). Modulation of the arginase pathway in the context of microbial pathogenesis: A metabolic enzyme moonlighting as an immune modulator. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1000899"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/BF02537346","article-title":"Inhibition of cytochrome c oxidase and hemolysis caused by lysosphingolipids","volume":"23","author":"Igisu","year":"1988","journal-title":"Lipids"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2930","DOI":"10.4049\/jimmunol.152.6.2930","article-title":"Intracellular infection by Leishmania donovani inhibits macrophage apoptosis","volume":"152","author":"Moore","year":"1994","journal-title":"J. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","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":"ref_49","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1017\/S0031182008004915","article-title":"Induction of apoptosis in host cells: A survival mechanism for Leishmania parasites?","volume":"135","author":"Getti","year":"2008","journal-title":"Parasitology"}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/9\/2\/422\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:25:49Z","timestamp":1760160349000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/9\/2\/422"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,18]]},"references-count":49,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["microorganisms9020422"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms9020422","relation":{},"ISSN":["2076-2607"],"issn-type":[{"type":"electronic","value":"2076-2607"}],"subject":[],"published":{"date-parts":[[2021,2,18]]}}}