{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:10:48Z","timestamp":1772169048128,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.16629.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T00:00:00Z","timestamp":1623974400000}}],"reference-count":46,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T00:00:00Z","timestamp":1623974400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["PG\/16\/26\/32099"],"award-info":[{"award-number":["PG\/16\/26\/32099"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT104726"],"award-info":[{"award-number":["WT104726"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Khyber Medical University\/Higher Education Commission, Pakistan"}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns3:p>\n                    <ns3:bold>Background<\/ns3:bold>\n                    : Polyparasitism is commonplace in countries where endemicity for multiple parasites exists, and studies in animal models of coinfection have made significant inroads into understanding the impact of often competing demands on the immune system. However, few studies have addressed how previous exposure to and treatment for one infection impacts a subsequent heterologous infection. \u00a0\n                  <\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Methods<\/ns3:bold>\n                    : We used a C57BL\/6 mouse model of drug-treated\n                    <ns3:italic>Leishmania donovani<\/ns3:italic>\n                    infection followed by experimental\n                    <ns3:italic>Plasmodium chabaudi<\/ns3:italic>\n                    AS malaria, focusing on hematological dysfunction as a common attribute of both infections. We measured parasite burden, blood parameters associated with anemia and thrombocytopenia, and serum thrombopoietin. In addition, we quantified macrophage iNOS expression through immunohistological analysis of the liver and spleen. \u00a0\n                  <\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Results<\/ns3:bold>\n                    : We found that the thrombocytopenia and anemia that accompanies primary\n                    <ns3:italic>L. donovani<\/ns3:italic>\n                    infection was rapidly reversed following single dose AmBisome\u00ae treatment, along with multiple other markers associated with immune activation (including restoration of tissue microarchitecture and reduced macrophage iNOS expression). Compared to naive mice, mice cured of previous L. donovani infection showed comparable albeit delayed clinical responses (including peak parasitemia and anemia) to\n                    <ns3:italic>P. chabaudi<\/ns3:italic>\n                    AS infection. Thrombocytopenia was also evident in these sequentially infected mice, consistent with a decrease in circulating levels of thrombopoietin. Architectural changes to the spleen were also comparable in sequentially infected mice compared to those with Plasmodium infection alone.\n                  <\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Conclusions<\/ns3:bold>\n                    : Our data suggest that in this sequential infection model, previously-treated L. donovani infection has limited impact on the subsequent development of Plasmodium infection, but this issue deserves further attention in models of more severe disease or through longitudinal population studies in humans.\n                  <\/ns3:p>","DOI":"10.12688\/wellcomeopenres.16629.2","type":"journal-article","created":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T07:30:07Z","timestamp":1624001407000},"page":"83","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Hematological consequences of malaria in mice previously treated for visceral 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Kirby","year":"2009","journal-title":"Am J Pathol."},{"key":"ref-7","doi-asserted-by":"publisher","first-page":"e1008145","DOI":"10.1371\/journal.ppat.1008145","article-title":"Trypanosoma brucei infection protects mice against malaria.","volume":"15","author":"M Sanches-Vaz","year":"2019","journal-title":"PLoS Pathog."},{"key":"ref-8","doi-asserted-by":"publisher","first-page":"161-6","DOI":"10.1016\/j.actatropica.2004.04.002","article-title":"Increased parasitaemia and delayed parasite clearance in Schistosoma mansoni and Plasmodium berghei co-infected mice.","volume":"91","author":"M Legesse","year":"2004","journal-title":"Acta Trop."},{"key":"ref-9","doi-asserted-by":"publisher","first-page":"3531-9","DOI":"10.1128\/IAI.73.6.3531-3539.2005","article-title":"Impairment of protective immunity to blood-stage malaria by concurrent nematode infection.","volume":"73","author":"Z Su","year":"2005","journal-title":"Infect Immun."},{"key":"ref-10","doi-asserted-by":"publisher","first-page":"410-21","DOI":"10.1086\/426871","article-title":"Malaria-Filaria Coinfection in Mice Makes Malarial Disease More Severe unless Filarial Infection Achieves Patency.","volume":"191","author":"A Graham","year":"2005","journal-title":"J Infect Dis."},{"key":"ref-11","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1186\/1471-2458-13-332","article-title":"Concomitant malaria among visceral leishmaniasis in-patients from Gedarif and Sennar States, Sudan: a retrospective case-control study.","volume":"13","author":"E van den Bogaart","year":"2013","journal-title":"BMC Public Health."},{"key":"ref-12","doi-asserted-by":"publisher","first-page":"6816913","DOI":"10.1155\/2017\/6816913","article-title":"Visceral Leishmaniasis-Malaria Coinfection and Their Associated Factors in Patients Attending Metema Hospital, Northwest Ethiopia: Suggestion for Integrated Vector Management","volume":"2017","author":"G Ferede","year":"2017","journal-title":"Malar Res Treat."},{"key":"ref-13","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1186\/s12879-019-3865-y","article-title":"Malaria-visceral leishmaniasis co-infection and associated factors among migrant laborers in West Armachiho district, North West Ethiopia: community based cross-sectional study.","volume":"19","author":"Y Aschale","year":"2019","journal-title":"BMC Infect Dis."},{"key":"ref-14","doi-asserted-by":"publisher","first-page":"e2536","DOI":"10.1371\/journal.pntd.0002536","article-title":"Risk factors for visceral leishmaniasis relapse in immunocompetent patients following treatment with 20 mg\/kg liposomal amphotericin B (Ambisome) in Bihar, India.","volume":"8","author":"S Burza","year":"2014","journal-title":"PLoS Negl Trop Dis."},{"key":"ref-15","doi-asserted-by":"publisher","first-page":"e705","DOI":"10.1371\/journal.pntd.0000705","article-title":"Visceral leishmaniasis relapse in Southern Sudan (1999\u20132007): a retrospective study of risk factors and trends.","volume":"4","author":"S Gorski","year":"2010","journal-title":"PLoS Negl Trop Dis."},{"key":"ref-16","doi-asserted-by":"publisher","first-page":"186-92","DOI":"10.1111\/j.1365-3156.2010.02694.x","article-title":"Risk factors for relapse of visceral leishmaniasis in Georgia.","volume":"16","author":"M Kajaia","year":"2011","journal-title":"Trop Med Int Health."},{"key":"ref-17","doi-asserted-by":"publisher","first-page":"44-9","DOI":"10.1016\/j.ijid.2020.02.028","article-title":"Predictors of relapse of visceral leishmaniasis in inner S\u00e3o Paulo State, Brazil.","volume":"95","author":"J Sim\u00e3o","year":"2020","journal-title":"Int J Infect Dis."},{"key":"ref-18","doi-asserted-by":"publisher","first-page":"e1006465","DOI":"10.1371\/journal.ppat.1006465","article-title":"TNF signalling drives expansion of bone marrow CD4+ T cells responsible for HSC exhaustion in experimental visceral leishmaniasis.","volume":"13","author":"A Pinto","year":"2017","journal-title":"PLoS Pathog."},{"key":"ref-19","doi-asserted-by":"publisher","first-page":"1840-1848","DOI":"10.1128\/iai.68.4.1840-1848.2000","article-title":"Enhanced Hematopoietic Activity Accompanies Parasite Expansion in the Spleen and Bone Marrow of Mice Infected with Leishmania donovani.","volume":"68","author":"S Cotterell","year":"2000","journal-title":"Infect Immun."},{"key":"ref-20","doi-asserted-by":"publisher","first-page":"e1006422","DOI":"10.1371\/journal.ppat.1006422","article-title":"Infection-adapted emergency hematopoiesis promotes visceral leishmaniasis.","volume":"13","author":"B Abidin","year":"2017","journal-title":"PLoS Pathog."},{"key":"ref-21","doi-asserted-by":"publisher","first-page":"1642-51","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-alpha.","volume":"95","author":"S Cotterell","year":"2000","journal-title":"Blood."},{"key":"ref-22","doi-asserted-by":"publisher","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":"O Preham","year":"2018","journal-title":"Front Immunol."},{"key":"ref-23","doi-asserted-by":"publisher","first-page":"2949-60","DOI":"10.4049\/jimmunol.1900940","article-title":"Malat1 Suppresses Immunity to Infection through Promoting Expression of Maf and IL-10 in Th Cells.","volume":"204","author":"J Hewitson","year":"2020","journal-title":"J Immunol."},{"key":"ref-24","article-title":"Impact of prior visceral leishmaniasis on subsequent malaria infection in mice","author":"P Kaye","year":"2021"},{"key":"ref-25","doi-asserted-by":"publisher","first-page":"198","DOI":"10.12688\/wellcomeopenres.15606.1","article-title":"Tissue-specific transcriptomic changes associated with AmBisome\u00ae treatment of BALB\/c mice with experimental visceral leishmaniasis [version 1; peer review: 3 approved].","volume":"4","author":"S Forrester","year":"2019","journal-title":"Wellcome Open Res."},{"key":"ref-26","doi-asserted-by":"publisher","first-page":"1627-37","DOI":"10.1182\/bloodadvances.2020004082","article-title":"Dissecting pathways to thrombocytopenia in a mouse model of visceral leishmaniasis.","volume":"5","author":"G Rani","year":"2021","journal-title":"Blood Adv."},{"key":"ref-27","doi-asserted-by":"publisher","first-page":"796182","DOI":"10.1155\/2015\/796182","article-title":"Leukogram Profile and Clinical Status in vivax and falciparum Malaria Patients from Colombia.","volume":"2015","author":"A Tob\u00f3n-Casta\u00f1o","year":"2015","journal-title":"J Trop Med."},{"key":"ref-28","doi-asserted-by":"publisher","first-page":"e0121057","DOI":"10.1371\/journal.pone.0121057","article-title":"Effects of Malaria Parasite Density on Blood Cell Parameters.","volume":"10","author":"M Kotepui","year":"2015","journal-title":"PLoS One."},{"key":"ref-29","doi-asserted-by":"publisher","first-page":"73-8","DOI":"10.1016\/s0167-5699(99)01549-2","article-title":"Organ-specific immune responses associated with infectious disease.","volume":"21","author":"C Engwerda","year":"2000","journal-title":"Immunol Today."},{"key":"ref-30","first-page":"1-10","article-title":"WHO This year\u2019s World malaria report at a glance.","year":"2019"},{"key":"ref-31","article-title":"Leishmaniasis fact sheet.","year":"2020"},{"key":"ref-32","doi-asserted-by":"publisher","first-page":"e1617","DOI":"10.1371\/journal.pntd.0001617","article-title":"Prevalence, features and risk factors for malaria co-infections amongst visceral leishmaniasis patients from Amudat Hospital, Uganda.","volume":"6","author":"E van den Bogaart","year":"2012","journal-title":"PLoS Negl Trop Dis."},{"key":"ref-33","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1186\/s12879-019-4478-1","article-title":"A case report of visceral leishmaniasis and malaria co-infection with pancytopenia and splenomegaly - a diagnostic challenge.","volume":"19","author":"P Ghimire","year":"2019","journal-title":"BMC Infect Dis."},{"key":"ref-34","doi-asserted-by":"publisher","first-page":"1703-10","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":"C Abongomera","year":"2017","journal-title":"Clin Infect Dis."},{"key":"ref-35","doi-asserted-by":"publisher","first-page":"193-201","DOI":"10.2147\/HIV.S143929","article-title":"Visceral leishmaniasis and HIV coinfection: current perspectives.","volume":"10","author":"J Lindoso","year":"2018","journal-title":"HIV AIDS (Auckl)."},{"key":"ref-36","doi-asserted-by":"publisher","first-page":"97-104","DOI":"10.1002\/jlb.45.2.97","article-title":"Macrophage Subset Repopulation in the Spleen: Differential Kinetics After Liposome-Mediated Elimination.","volume":"45","author":"N van Rooijen","year":"1989","journal-title":"J Leukoc Biol."},{"key":"ref-37","doi-asserted-by":"publisher","first-page":"2518-26","DOI":"10.4049\/jimmunol.177.4.2518","article-title":"CD8+ T lymphocyte-mediated loss of marginal metallophilic macrophages following infection with Plasmodium chabaudi chabaudi AS.","volume":"177","author":"L Beattie","year":"2006","journal-title":"J Immunol."},{"key":"ref-38","doi-asserted-by":"publisher","first-page":"aaf1098","DOI":"10.1126\/science.aaf1098","article-title":"Trained immunity: A program of innate immune memory in health and disease.","volume":"352","author":"M Netea","year":"2016","journal-title":"Science."},{"key":"ref-39","doi-asserted-by":"publisher","first-page":"1-7","DOI":"10.1007\/s12026-021-09170-y","article-title":"Trained innate immunity.","volume":"69","author":"B Arneth","year":"2021","journal-title":"Immunol Res."},{"key":"ref-40","doi-asserted-by":"publisher","first-page":"48-54","DOI":"10.1161\/ATVBAHA.120.314215","article-title":"Trained Immunity and Cardiometabolic Disease: The Role of Bone Marrow.","volume":"41","author":"I Mitroulis","year":"2021","journal-title":"Arterioscler Thromb Vasc Biol."},{"key":"ref-41","doi-asserted-by":"publisher","first-page":"32-43","DOI":"10.1016\/j.immuni.2020.10.011","article-title":"The Intersection of Epigenetics and Metabolism in Trained Immunity.","volume":"54","author":"S Fanucchi","year":"2021","journal-title":"Immunity."},{"key":"ref-42","doi-asserted-by":"publisher","first-page":"75-80","DOI":"10.1016\/j.pt.2004.11.008","article-title":"The importance of the spleen in malaria.","volume":"21","author":"C Engwerda","year":"2005","journal-title":"Trends Parasitol."},{"key":"ref-43","doi-asserted-by":"publisher","first-page":"228-31","DOI":"10.1038\/nature12231","article-title":"Vector transmission regulates immune control of Plasmodium virulence.","volume":"498","author":"P Spence","year":"2013","journal-title":"Nature."},{"key":"ref-44","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1186\/1475-2875-11-407","article-title":"Mosquito transmission of the rodent malaria parasite Plasmodium chabaudi.","volume":"11","author":"P Spence","year":"2012","journal-title":"Malar J."},{"key":"ref-45","doi-asserted-by":"publisher","first-page":"e0003699","DOI":"10.1371\/journal.pntd.0003699","article-title":"Effectiveness and safety of short course liposomal amphotericin B (AmBisome) as first line treatment for visceral leishmaniasis in Bangladesh.","volume":"9","author":"E Lucero","year":"2015","journal-title":"PLoS Negl Trop Dis."},{"key":"ref-46","doi-asserted-by":"publisher","first-page":"457-462","DOI":"10.1128\/IAI.14.2.457-462.1976","article-title":"Influence of rodent malaria on the course of Leishmania enriettii infection of hamsters.","volume":"14","author":"A Belehu","year":"1976","journal-title":"Infect Immun."}],"container-title":["Wellcome Open 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.18750.r44578, Yasuyuki Goto, Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan, 09 Jul 2021, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-83\/v2#referee-response-44578","order":0,"name":"referee-response-44578","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.18333.r43545, Breanna M. Scorza, Department of Epidemiology, University of Iowa, Iowa City, IA, USA, 05 May 2021, version 1, 1 approved, 1 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-83\/v1#referee-response-43545","order":1,"name":"referee-response-43545","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Paul Kaye<\/b>; \n<i>Posted: 08 Jun 2021<\/i>; We thank the reviewer for her supportive comments. &nbsp;We did not measure acquired immune responses to Plasmodium infection, but as the reviewer points out, we would not expect there to be major changes besides perhaps a delay in kinetics.&nbsp; We would prefer not to speculate on whether previous VL might impact memory generated during primary \n<i>Plasmodium <\/i>infection, but in our revised manuscript we have noted this as a possible area for further study (Discussion, paragraph 5) .","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-83\/v2#referee-comment-4651","order":2,"name":"referee-comment-4651","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was funded by a Wellcome Trust Senior Investigator Award (to PMK: WT104726), a British Heart Foundation grant (to ISH: PG\/16\/26\/32099) and by a scholarship to GR from Khyber Medical University\/Higher Education Commission, Pakistan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}