{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T23:19:50Z","timestamp":1794266390898,"version":"4.9.0"},"reference-count":104,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,5]],"date-time":"2021-04-05T00:00:00Z","timestamp":1617580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>The leishmaniases constitute a group of parasitic diseases caused by species of the protozoan genus Leishmania. In humans it can present different clinical manifestations and are usually classified as cutaneous, mucocutaneous, and visceral (VL). Although the full range of parasite\u2014host interactions remains unclear, recent advances are improving our comprehension of VL pathophysiology. In this review we explore the differences in VL immunobiology between the liver and the spleen, leading to contrasting infection outcomes in the two organs, specifically clearance of the parasite in the liver and failure of the spleen to contain the infection. Based on parasite biology and the mammalian immune response, we describe how hypoxia-inducible factor 1 (HIF1) and the PI3K\/Akt pathway function as major determinants of the observed immune failure. We also summarize existing knowledge on pancytopenia in VL, as a direct effect of the parasite on bone marrow health and regenerative capacity. Finally, we speculate on the possible effect that manipulation by the parasite of the PI3K\/Akt\/HIF1 axis may have on the myelodysplastic (MDS) features observed in VL.<\/jats:p>","DOI":"10.3390\/microorganisms9040759","type":"journal-article","created":{"date-parts":[[2021,4,5]],"date-time":"2021-04-05T11:48:29Z","timestamp":1617623309000},"page":"759","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Effects of Visceralising Leishmania on the Spleen, Liver, and Bone Marrow: A Pathophysiological Perspective"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7597-4163","authenticated-orcid":false,"given":"Aikaterini","family":"Poulaki","sequence":"first","affiliation":[{"name":"Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelia-Theophano","family":"Piperaki","sequence":"additional","affiliation":[{"name":"Department of Microbiology, School of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Voulgarelis","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,5]]},"reference":[{"key":"ref_1","unstructured":"WHO (2021, January 16). The disease and its epidemiology. Available online: https:\/\/www.who.int\/leishmaniasis\/disease_epidemiology\/en\/."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Akuffo, H., Costa, C., van Griensven, J., Burza, S., Moreno, J., and Herrero, M. (2018). New insights into leishmaniasis in the immunosuppressed. PLoS Negl. Trop. Dis., 12.","DOI":"10.1371\/journal.pntd.0006375"},{"key":"ref_3","unstructured":"World Health Organization (2021, January 16). Leishmaniasis. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/leishmaniasis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e02851","DOI":"10.7554\/eLife.02851","article-title":"Global distribution maps of the leishmaniases","volume":"3","author":"Pigott","year":"2014","journal-title":"Elife"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1093\/cid\/ciu102","article-title":"Asymptomatic Leishmania infection: A new challenge for Leishmania control","volume":"58","author":"Singh","year":"2014","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"639304","DOI":"10.1155\/2012\/639304","article-title":"Differential Regulation of the Immune Response in the Spleen and Liver of Mice Infected with Leishmania donovani","volume":"2012","author":"Bankoti","year":"2012","journal-title":"J. Trop. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.pt.2004.08.009","article-title":"Macrophages, pathology and parasite persistence in experimental visceral leishmaniasis","volume":"20","author":"Engwerda","year":"2004","journal-title":"Trends Parasitol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1111\/j.0105-2896.2004.00188.x","article-title":"The immunopathology of experimental visceral leishmaniasis","volume":"201","author":"Kaye","year":"2004","journal-title":"Immunol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1080\/14728222.2018.1472241","article-title":"Emerging therapeutic targets for treatment of leishmaniasis","volume":"22","author":"Sundar","year":"2018","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.vetpar.2016.02.009","article-title":"Vaccination against canine leishmaniosis increases the phagocytic activity, nitric oxide production and expression of cell activation\/migration molecules in neutrophils and monocytes","volume":"220","author":"Moreira","year":"2016","journal-title":"Vet. Parasitol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"16549","DOI":"10.1038\/s41598-018-34812-x","article-title":"A complete Leishmania donovani reference genome identifies novel genetic variations associated with virulence","volume":"8","author":"Lypaczewski","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1046\/j.1365-2958.2001.02286.x","article-title":"Characterization of the A2-A2rel gene cluster in Leishmania donovani: Involvement of A2 in visceralization during infection","volume":"39","author":"Zhang","year":"2001","journal-title":"Mol. Microbiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1111\/j.1365-3024.2008.01051.x","article-title":"Inflammation and structural changes of splenic lymphoid tissue in visceral leishmaniasis: A study on naturally infected dogs","volume":"30","author":"Santana","year":"2008","journal-title":"Parasite Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Silva-O\u2019Hare, J., de Oliveira, I.S., Klevorn, T., Almeida, V.A., Oliveira, G.G., Atta, A.M., de Freitas, L.A., and Dos-Santos, W.L. (2016). Disruption of Splenic Lymphoid Tissue and Plasmacytosis in Canine Visceral Leishmaniasis: Changes in Homing and Survival of Plasma Cells. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0156733"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Cavalcanti, A.S., Ribeiro-Alves, M., Pereira, L.d.O., Mestre, G.L., Ferreira, A.B., Morgado, F.N., Boite, M.C., Cupolillo, E., Moraes, M.O., and Porrozzi, R. (2015). Parasite load induces progressive spleen architecture breakage and impairs cytokine mRNA expression in Leishmania infantum-naturally infected dogs. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0123009"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3389\/fcimb.2018.00394","article-title":"Histological Disorganization of Spleen Compartments and Severe Visceral Leishmaniasis","volume":"8","author":"Hermida","year":"2018","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3389\/fped.2015.00059","article-title":"Visceral Leishmaniasis as a Possible Reason for Pancytopenia","volume":"3","author":"Koster","year":"2015","journal-title":"Front. Pediatr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1007\/s12288-010-0027-1","article-title":"Hematologic changes in visceral leishmaniasis\/kala azar","volume":"26","author":"Varma","year":"2010","journal-title":"Indian J. Hematol. Blood Transfus."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1080\/00034983.1986.11812022","article-title":"Mechanism of anaemia in resistant visceral leishmaniasis","volume":"80","author":"Pippard","year":"1986","journal-title":"Ann. Trop. Med. Parasitol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/s00436-016-5313-x","article-title":"Prevalence, severity, and pathogeneses of anemia in visceral leishmaniasis","volume":"116","author":"Goto","year":"2017","journal-title":"Parasitol. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1002\/ajh.10200","article-title":"Myelodysplastic features in visceral leishmaniasis","volume":"71","author":"Yarali","year":"2002","journal-title":"Am. J. Hematol."},{"key":"ref_22","first-page":"206","article-title":"Dyserythropoiesis in 105 patients with visceral leishmaniasis","volume":"10","author":"Sheikha","year":"2004","journal-title":"Lab. Hematol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2958","DOI":"10.3389\/fimmu.2018.02958","article-title":"CD4(+) T Cells Alter the Stromal Microenvironment and Repress Medullary Erythropoiesis in Murine Visceral Leishmaniasis","volume":"9","author":"Preham","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1046\/j.1365-2613.2001.00199.x","article-title":"Tissue granuloma structure-function in experimental visceral leishmaniasis","volume":"82","author":"Murray","year":"2001","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/s13071-018-2624-z","article-title":"Histopathological and immunohistochemical characterisation of hepatic granulomas in Leishmania donovani-infected BALB\/c mice: A time-course study","volume":"11","author":"Salguero","year":"2018","journal-title":"Parasites Vectors"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s00281-015-0548-7","article-title":"Lessons from other diseases: Granulomatous inflammation in leishmaniasis","volume":"38","author":"Kaye","year":"2016","journal-title":"Semin. Immunopathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3709","DOI":"10.4049\/jimmunol.1300768","article-title":"Tissue requirements for establishing long-term CD4+ T cell-mediated immunity following Leishmania donovani infection","volume":"192","author":"Bunn","year":"2014","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Robert-Gangneux, F., Drogoul, A.S., Rostan, O., Piquet-Pellorce, C., Cayon, J., Lisbonne, M., Herbelin, A., Gascan, H., Guiguen, C., and Samson, M. (2012). Invariant NKT cells drive hepatic cytokinic microenvironment favoring efficient granuloma formation and early control of Leishmania donovani infection. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033413"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"35","DOI":"10.3389\/fimmu.2013.00035","article-title":"Functional complexity of the Leishmania granuloma and the potential of in silico modeling","volume":"4","author":"Moore","year":"2013","journal-title":"Front. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.3389\/fimmu.2018.01393","article-title":"Invariant Natural Killer T Cell Subsets\u2014More Than Just Developmental Intermediates","volume":"9","author":"Krovi","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Stanley, A.C., Zhou, Y., Amante, F.H., Randall, L.M., Haque, A., Pellicci, D.G., Hill, G.R., Smyth, M.J., Godfrey, D.I., and Engwerda, C.R. (2008). Activation of invariant NKT cells exacerbates experimental visceral leishmaniasis. PLoS Pathog., 4.","DOI":"10.1371\/journal.ppat.1000028"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1093\/intimm\/dxq444","article-title":"Invariant NKT cell anergy is induced by a strong TCR-mediated signal plus co-stimulation","volume":"22","author":"Iyoda","year":"2010","journal-title":"Int. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"227","DOI":"10.3389\/fimmu.2019.00227","article-title":"Molecular Aspects of Dendritic Cell Activation in Leishmaniasis: An Immunobiological View","volume":"10","author":"Tiburcio","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0165-2478(03)00021-X","article-title":"Infection pattern and immune response in the spleen and liver of BALB\/c mice intracardially infected with Leishmania donovani amastigotes","volume":"86","author":"Mukherjee","year":"2003","journal-title":"Immunol. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1002\/hep.28130","article-title":"Hepatic stellate cells regulate liver immunity to visceral leishmaniasis through P110delta-dependent induction and expansion of regulatory T cells in mice","volume":"63","author":"Khadem","year":"2016","journal-title":"Hepatology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1136\/jcp.47.6.547","article-title":"Liver morphology and function in visceral leishmaniasis (Kala-azar)","volume":"47","author":"Hashim","year":"1994","journal-title":"J. Clin. Pathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"14693","DOI":"10.1038\/s41598-017-14935-3","article-title":"Ly6C(hi) inflammatory monocytes promote susceptibility to Leishmania donovani infection","volume":"7","author":"Terrazas","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.cellimm.2016.09.004","article-title":"PI3K signaling in Leishmania infections","volume":"309","author":"Kima","year":"2016","journal-title":"Cell. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1111\/j.0105-2896.2004.00190.x","article-title":"Does the Leishmania major paradigm of pathogenesis and protection hold for New World cutaneous leishmaniases or the visceral disease?","volume":"201","author":"Alexander","year":"2004","journal-title":"Immunol. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Paun, A., Bankoti, R., Joshi, T., Pitha, P.M., and Stager, S. (2011). Critical role of IRF-5 in the development of T helper 1 responses to Leishmania donovani infection. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1001246"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"100036","DOI":"10.1016\/j.cytox.2020.100036","article-title":"Cytokines and splenic remodelling during Leishmania donovani infection","volume":"2","author":"Engwerda","year":"2020","journal-title":"Cytokine X"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Singh, A.K., Mukhopadhyay, C., Biswas, S., Singh, V.K., and Mukhopadhyay, C.K. (2012). Intracellular pathogen Leishmania donovani activates hypoxia inducible factor-1 by dual mechanism for survival advantage within macrophage. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0038489"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.1084\/jem.20100587","article-title":"HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment","volume":"207","author":"Corzo","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"216","DOI":"10.3389\/fimmu.2018.00216","article-title":"Hypoxia, Hypoxia-Inducible Factor-1alpha, and Innate Antileishmanial Immune Responses","volume":"9","author":"Schatz","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1242\/jcs.00860","article-title":"Dendritic cells as host cells for the promastigote and amastigote stages of Leishmania amazonensis: The role of opsonins in parasite uptake and dendritic cell maturation","volume":"117","author":"Prina","year":"2004","journal-title":"J. Cell Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"741","DOI":"10.3389\/fimmu.2019.00741","article-title":"Langerin(+)CD8(+) Dendritic Cells in the Splenic Marginal Zone: Not So Marginal After All","volume":"10","author":"Backer","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_47","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":"ref_48","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.4049\/jimmunol.172.2.1009","article-title":"Liver dendritic cells are less immunogenic than spleen dendritic cells because of differences in subtype composition","volume":"172","author":"Pillarisetty","year":"2004","journal-title":"J. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Abidin, B.M., Hammami, A., Stager, S., and Heinonen, K.M. (2017). Infection-adapted emergency hematopoiesis promotes visceral leishmaniasis. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006422"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"10","DOI":"10.3389\/fimmu.2019.03071","article-title":"IRF-5 Expression in Myeloid Cells Is Required for Splenomegaly in L. donovani Infected Mice","volume":"10","author":"Mai","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5486","DOI":"10.4049\/jimmunol.176.9.5486","article-title":"Loss of dendritic cell migration and impaired resistance to Leishmania donovani infection in mice deficient in CCL19 and CCL21","volume":"176","author":"Ato","year":"2006","journal-title":"J. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Osorio, E.Y., Medina-Colorado, A.A., Travi, B.L., and Melby, P.C. (2020). In-situ proliferation contributes to the accumulation of myeloid cells in the spleen during progressive experimental visceral leishmaniasis. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0242337"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Kong, F., Saldarriaga, O.A., Spratt, H., Osorio, E.Y., Travi, B.L., Luxon, B.A., and Melby, P.C. (2017). Transcriptional Profiling in Experimental Visceral Leishmaniasis Reveals a Broad Splenic Inflammatory Environment that Conditions Macrophages toward a Disease-Promoting Phenotype. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006165"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.4049\/jimmunol.170.5.2613","article-title":"Activation of TGF-beta by Leishmania chagasi: Importance for parasite survival in macrophages","volume":"170","author":"Gantt","year":"2003","journal-title":"J. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Das, V.N.R., Bimal, S., Siddiqui, N.A., Kumar, A., Pandey, K., Sinha, S.K., Topno, R.K., Mahentesh, V., Singh, A.K., and Lal, C.S. (2020). Conversion of asymptomatic infection to symptomatic visceral leishmaniasis: A study of possible immunological markers. PLoS Negl. Trop. Dis., 14.","DOI":"10.1371\/journal.pntd.0008272"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Hammami, A., Abidin, B.M., Charpentier, T., Fabie, A., Duguay, A.P., Heinonen, K.M., and Stager, S. (2017). HIF-1alpha is a key regulator in potentiating suppressor activity and limiting the microbicidal capacity of MDSC-like cells during visceral leishmaniasis. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006616"},{"key":"ref_57","first-page":"47","article-title":"HIF-mediated innate immune responses: Cell signaling and therapeutic implications","volume":"2","author":"Harris","year":"2014","journal-title":"Hypoxia"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1046\/j.1365-2567.2000.00939.x","article-title":"Modulation of CD11C+ splenic dendritic cell functions in murine visceral leishmaniasis: Correlation with parasite replication in the spleen","volume":"99","author":"Basu","year":"2000","journal-title":"Immunology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3500","DOI":"10.1038\/s41598-018-21891-z","article-title":"HIF-1alpha hampers dendritic cell function and Th1 generation during chronic visceral leishmaniasis","volume":"8","author":"Hammami","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1158\/2159-8290.CD-11-0218","article-title":"PI3K and STAT3: A new alliance","volume":"1","author":"Vogt","year":"2011","journal-title":"Cancer Discov."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e12586","DOI":"10.1111\/pim.12586","article-title":"Leishmania infection activates host mTOR for its survival by M2 macrophage polarization","volume":"40","author":"Kumar","year":"2018","journal-title":"Parasite Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"367","DOI":"10.4049\/jimmunol.1100076","article-title":"Myeloid cell IL-10 production in response to leishmania involves inactivation of glycogen synthase kinase-3beta downstream of phosphatidylinositol-3 kinase","volume":"188","author":"Nandan","year":"2012","journal-title":"J. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.chom.2013.08.004","article-title":"A transcriptomic network identified in uninfected macrophages responding to inflammation controls intracellular pathogen survival","volume":"14","author":"Beattie","year":"2013","journal-title":"Cell Host Microbe"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.ccr.2010.04.023","article-title":"NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling","volume":"17","author":"Zhou","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1093\/jac\/dkw448","article-title":"Pharmacological inhibition of p110delta subunit of PI3K confers protection against experimental leishmaniasis","volume":"72","author":"Khadem","year":"2017","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Martinez de Narvajas, I., Diaz, A., Bassegoda, O., Carpio, A., Fuster, C., Valls, M.E., Alvarez-Martinez, M.J., Garcia-Vidal, C., Soriano, A., and Martinez, J.A. (2019). Acute liver failure due to visceral leishmaniasis in Barcelona: A case report. BMC Infect. Dis., 19.","DOI":"10.1186\/s12879-019-4553-7"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1016\/j.cgh.2008.04.033","article-title":"High prevalence of functional liver derangement in visceral leishmaniasis at an Indian tertiary care center","volume":"6","author":"Mathur","year":"2008","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.hoc.2017.11.009","article-title":"Ineffective Erythropoiesis: Anemia and Iron Overload","volume":"32","author":"Gupta","year":"2018","journal-title":"Hematol. Oncol. Clin. N. Am."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2378","DOI":"10.1182\/blood-2019-128133","article-title":"Understanding the Mechanisms Underlying Thrombocytopenia in Visceral Leishmaniasis","volume":"134","author":"Rani","year":"2019","journal-title":"Blood"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.thromres.2009.11.004","article-title":"The role of inflammation in regulating platelet production and function: Toll-like receptors in platelets and megakaryocytes","volume":"125","author":"Beaulieu","year":"2010","journal-title":"Thromb. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1046\/j.1365-2141.1998.00624.x","article-title":"Serum erythropoietin concentration in anaemia of visceral leishmaniasis (kala-azar) before and during antimonial therapy","volume":"100","author":"Saeed","year":"1998","journal-title":"Br. J. Haematol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"4321","DOI":"10.1182\/blood-2011-03-283614","article-title":"beta-thalassemia: A model for elucidating the dynamic regulation of ineffective erythropoiesis and iron metabolism","volume":"118","author":"Ginzburg","year":"2011","journal-title":"Blood"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1182\/blood.V39.6.794.794","article-title":"Hemichromes in single inclusion bodies in red cells of beta thalassemia","volume":"39","author":"Rachmilewitz","year":"1972","journal-title":"Blood"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1046\/j.1365-2141.1999.01217.x","article-title":"Metabolic indicators of oxidative stress correlate with haemichrome attachment to membrane, band 3 aggregation and erythrophagocytosis in beta-thalassaemia intermedia","volume":"104","author":"Cappellini","year":"1999","journal-title":"Br. J. Haematol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s11010-008-9909-z","article-title":"Oxidation of hemoglobin and redistribution of band 3 promote erythrophagocytosis in visceral leishmaniasis","volume":"321","author":"Chowdhury","year":"2009","journal-title":"Mol. Cell. Biochem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/978-1-4684-5985-2_16","article-title":"Role of hemoglobin denaturation and band 3 clustering in initiating red cell removal","volume":"307","author":"Low","year":"1991","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"6051093","DOI":"10.1155\/2016\/6051093","article-title":"Band 3 Erythrocyte Membrane Protein Acts as Redox Stress Sensor Leading to Its Phosphorylation by p (72) Syk","volume":"2016","author":"Pantaleo","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1182\/blood.V95.5.1642.005k10_1642_1651","article-title":"Leishmania donovani infection of bone marrow stromal macrophages selectively enhances myelopoiesis, by a mechanism involving GM-CSF and TNF-\u03b1","volume":"95","author":"Cotterell","year":"2000","journal-title":"Blood"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Lafuse, W.P., Story, R., Mahylis, J., Gupta, G., Varikuti, S., Steinkamp, H., Oghumu, S., and Satoskar, A.R. (2013). Leishmania donovani infection induces anemia in hamsters by differentially altering erythropoiesis in bone marrow and spleen. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0059509"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.cellimm.2017.10.016","article-title":"Infection of hematopoietic stem cells by Leishmania infantum increases erythropoiesis and alters the phenotypic and functional profiles of progeny","volume":"326","author":"Moreira","year":"2018","journal-title":"Cell. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"286","DOI":"10.3389\/fonc.2017.00286","article-title":"Non-Canonical Mechanisms Regulating Hypoxia-Inducible Factor 1 Alpha in Cancer","volume":"7","author":"Iommarini","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.exppara.2011.05.018","article-title":"Energetic metabolism of axenic promastigotes of Leishmania (Viannia) braziliensis","volume":"128","author":"Costa","year":"2011","journal-title":"Exp. Parasitol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molbiopara.2006.03.017","article-title":"Energy metabolism of trypanosomatids: Adaptation to available carbon sources","volume":"149","author":"Bringaud","year":"2006","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Subramanian, A., Jhawar, J., and Sarkar, R.R. (2015). Dissecting Leishmania infantum Energy Metabolism\u2014A Systems Perspective. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0137976"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1016\/j.bbamcr.2006.08.019","article-title":"Metabolic functions of glycosomes in trypanosomatids","volume":"1763","author":"Michels","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.biochi.2015.03.021","article-title":"Origin and evolution of metabolic sub-cellular compartmentalization in eukaryotes","volume":"119","author":"Gabaldon","year":"2015","journal-title":"Biochimie"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Mahy, B.W., Ter Meulen, V., Borriello, S.P., Murray, P.R., Funke, G., Kaufmann, S.H., Steward, M.W., Merz, W.G., Hay, R.J., and Cox, F. (2010). Cellular Organization of Parasitic Protozoa. Topley & Wilson\u2019s Microbiology and Microbial Infections, John Wiley & Sons, Ltd.. [1st ed.].","DOI":"10.1002\/9780470688618"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"435","DOI":"10.3389\/fcimb.2019.00435","article-title":"Redox Balance Keepers and Possible Cell Functions Managed by Redox Homeostasis in Trypanosoma cruzi","volume":"9","author":"Mesias","year":"2019","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1146\/annurev-micro-090110-102913","article-title":"Metabolic pathways required for the intracellular survival of Leishmania","volume":"65","author":"McConville","year":"2011","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Saunders, E.C., Ng, W.W., Kloehn, J., Chambers, J.M., Ng, M., and McConville, M.J. (2014). Induction of a stringent metabolic response in intracellular stages of Leishmania mexicana leads to increased dependence on mitochondrial metabolism. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1003888"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"27706","DOI":"10.1074\/jbc.M110.213553","article-title":"Isotopomer profiling of Leishmania mexicana promastigotes reveals important roles for succinate fermentation and aspartate uptake in tricarboxylic acid cycle (TCA) anaplerosis, glutamate synthesis, and growth","volume":"286","author":"Saunders","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.pt.2007.06.009","article-title":"Living in a phagolysosome; metabolism of Leishmania amastigotes","volume":"23","author":"McConville","year":"2007","journal-title":"Trends Parasitol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Real, F., and Mortara, R.A. (2012). The diverse and dynamic nature of Leishmania parasitophorous vacuoles studied by multidimensional imaging. PLoS Negl. Trop. Dis., 6.","DOI":"10.1371\/journal.pntd.0001518"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1016\/S0020-7519(01)00259-4","article-title":"Life in vacuoles\u2014Nutrient acquisition by Leishmania amastigotes","volume":"31","author":"Burchmore","year":"2001","journal-title":"Int. J. Parasitol."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Williams, R.A., Smith, T.K., Cull, B., Mottram, J.C., and Coombs, G.H. (2012). ATG5 is essential for ATG8-dependent autophagy and mitochondrial homeostasis in Leishmania major. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002695"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2523","DOI":"10.3389\/fimmu.2019.02523","article-title":"Deciphering the Role Played by Autophagy in Leishmania Infection","volume":"10","author":"Veras","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_97","first-page":"511","article-title":"The Leishmania Parasitophorous Vacuole Membrane at the Parasite-Host Interface","volume":"92","author":"Young","year":"2019","journal-title":"Yale J. Biol. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s12929-020-00691-6","article-title":"Autophagosome formation in relation to the endoplasmic reticulum","volume":"27","author":"Yamamoto","year":"2020","journal-title":"J. Biomed. Sci."},{"key":"ref_99","doi-asserted-by":"crossref","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":"ref_100","doi-asserted-by":"crossref","first-page":"e12889","DOI":"10.1111\/cmi.12889","article-title":"Leishmania parasitophorous vacuole membranes display phosphoinositides that create conditions for continuous Akt activation and a target for miltefosine in Leishmania infections","volume":"20","author":"Zhang","year":"2018","journal-title":"Cell. Microbiol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1007\/s12185-018-2534-z","article-title":"Metabolism as master of hematopoietic stem cell fate","volume":"109","author":"Ito","year":"2019","journal-title":"Int. J. Hematol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1158\/2159-8290.CD-17-1203","article-title":"Pathobiological Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes","volume":"8","author":"Hayashi","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1002\/eji.201747257","article-title":"Leishmania amazonensis downregulates macrophage iNOS expression via Histone Deacetylase 1 (HDAC1): A novel parasite evasion mechanism","volume":"48","author":"Vivarini","year":"2018","journal-title":"Eur. J. Immunol."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Marr, A.K., MacIsaac, J.L., Jiang, R., Airo, A.M., Kobor, M.S., and McMaster, W.R. (2014). Leishmania donovani infection causes distinct epigenetic DNA methylation changes in host macrophages. 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