{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T09:58:29Z","timestamp":1777370309361,"version":"3.51.4"},"reference-count":49,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,9]],"date-time":"2022-01-09T00:00:00Z","timestamp":1641686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/CVT-CVT\/28908\/2017"],"award-info":[{"award-number":["PTDC\/CVT-CVT\/28908\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/CVT-CVT\/0228\/2020"],"award-info":[{"award-number":["PTDC\/CVT-CVT\/0228\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Centro de Investiga\u00e7\u00e3o Interdisciplinar em Sanidade Animal","award":["CIISA, UIDB\/00276\/2020"],"award-info":[{"award-number":["CIISA, UIDB\/00276\/2020"]}]},{"name":"Global Health and Tropical Medicine","award":["GHTM, UID\/04413\/2020"],"award-info":[{"award-number":["GHTM, UID\/04413\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>L. infantum is the aetiological agent of zoonotic visceral leishmaniasis (ZVL), a disease that affects humans and dogs. Leishmania parasites are well adapted to aggressive conditions inside the phagolysosome and can control the immune activation of macrophages (M\u00d8s). Although M\u00d8s are highly active phagocytic cells with the capacity to destroy pathogens, they additionally comprise the host cells for Leishmania infection, replication, and stable establishment in the mammal host. The present study compares, for the first time, the innate immune response to L. infantum infection of two different macrophage lineages: the blood macrophages and the liver macrophages (Kupffer cells, KC). Our findings showed that L. infantum takes advantage of the natural predisposition of blood-M\u00d8s to phagocyte pathogens. However, parasites rapidly subvert the mechanisms of M\u00d8s immune activation. On the other hand, KCs, which are primed for immune tolerance, are not extensively activated and can overcome the dormancy induced by the parasite, exhibiting a selection of immune mechanisms, such as extracellular trap formation. Altogether, KCs reveal a different pattern of response in contrast with blood-M\u00d8s when confronting L. infantum parasites. In addition, KCs response appears to be more efficient in managing parasite infection, thus contributing to the ability of the liver to naturally restrain Leishmania dissemination.<\/jats:p>","DOI":"10.3390\/biology11010100","type":"journal-article","created":{"date-parts":[[2022,1,9]],"date-time":"2022-01-09T20:29:26Z","timestamp":1641760166000},"page":"100","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Zoonotic Visceral Leishmaniasis: New Insights on Innate Immune Response by Blood Macrophages and Liver Kupffer Cells to Leishmania infantum Parasites"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4261-3879","authenticated-orcid":false,"given":"Armanda Viana","family":"Rodrigues","sequence":"first","affiliation":[{"name":"Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Rua da Junqueira 100, 1349-008 Lisboa, Portugal"}]},{"given":"Ana","family":"Val\u00e9rio-Bolas","sequence":"additional","affiliation":[{"name":"Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Rua da Junqueira 100, 1349-008 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9462-4679","authenticated-orcid":false,"given":"Gra\u00e7a","family":"Alexandre-Pires","sequence":"additional","affiliation":[{"name":"CIISA, Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Av. Universidade T\u00e9cnica, 1300-477 Lisbon, Portugal"}]},{"given":"Maria","family":"Aires Pereira","sequence":"additional","affiliation":[{"name":"Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Rua da Junqueira 100, 1349-008 Lisboa, Portugal"},{"name":"Polytechnic Institute of Viseu, Agrarian School, Quinta da Alagoa-Estrada de Nelas Ranhados, 3500-606 Viseu, Portugal"}]},{"given":"Telmo","family":"Nunes","sequence":"additional","affiliation":[{"name":"Microscopy Center, Faculty of Sciences, Campo Grande, 1749-016 Lisboa, Portugal"}]},{"given":"D\u00e1rio","family":"Ligeiro","sequence":"additional","affiliation":[{"name":"IPST-Centro de Sangue e Transplanta\u00e7\u00e3o de Lisboa, Alameda das Linhas de Torres, 117, 1749-005 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6632-1224","authenticated-orcid":false,"given":"Isabel","family":"Pereira da Fonseca","sequence":"additional","affiliation":[{"name":"CIISA, Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Av. Universidade T\u00e9cnica, 1300-477 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9264-3887","authenticated-orcid":false,"given":"Gabriela","family":"Santos-Gomes","sequence":"additional","affiliation":[{"name":"Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Rua da Junqueira 100, 1349-008 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Van Furth, R., and Beekhuizen, H. (1998). Monocytes. Encyclopedia of Immunology, Elsevier.","DOI":"10.1006\/rwei.1999.0443"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/nri2448","article-title":"Exploring the full spectrum of macrophage activation","volume":"8","author":"Mosser","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.cell.2006.02.015","article-title":"Pathogen recognition and innate immunity","volume":"124","author":"Akira","year":"2006","journal-title":"Cell"},{"key":"ref_4","first-page":"10964","article-title":"Macrophages polarization is mediated by the combination of PRR ligands and distinct inflammatory cytokines","volume":"8","author":"Zhou","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.coi.2008.06.001","article-title":"NOD-like receptors (NLRs): Bona fide intracellular microbial sensors","volume":"20","author":"Shaw","year":"2008","journal-title":"Curr. Opin. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.immuni.2012.12.001","article-title":"Fate Mapping Reveals Origins and Dynamics of Monocytes and Tissue Macrophages under Homeostasis","volume":"38","author":"Yona","year":"2013","journal-title":"Immunity"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.immuni.2016.02.024","article-title":"Tissue-Resident Macrophage Ontogeny and Homeostasis","volume":"44","author":"Ginhoux","year":"2016","journal-title":"Immunity"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.immuni.2014.06.013","article-title":"Origin and Functions of Tissue Macrophages","volume":"41","author":"Epelman","year":"2014","journal-title":"Immunity"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1038\/ni.2691","article-title":"Immune surveillance by the liver","volume":"14","author":"Jenne","year":"2013","journal-title":"Nat. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1002\/cphy.c120026","article-title":"Kupffer cells in the liver","volume":"3","author":"Dixon","year":"2013","journal-title":"Compr. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2529","DOI":"10.3389\/fimmu.2018.02529","article-title":"Macrophage Polarization in Leishmaniasis: Broadening Horizons","volume":"9","author":"Bortoleti","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e12617","DOI":"10.1111\/pim.12617","article-title":"Canine neutrophils cooperate with macrophages in the early stages of Leishmania infantum in vitro infection","volume":"41","author":"Pereira","year":"2019","journal-title":"Parasite Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1128\/CMR.18.2.293-305.2005","article-title":"Subversion mechanisms by which Leishmania parasites can escape the host immune response: A signaling point of view","volume":"18","author":"Olivier","year":"2005","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"100041","DOI":"10.1016\/j.cytox.2020.100041","article-title":"Macrophages as host, effector and immunoregulatory cells in leishmaniasis: Impact of tissue micro-environment and metabolism","volume":"2","author":"Bogdan","year":"2020","journal-title":"Cytokine X"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.cimid.2017.09.004","article-title":"Leishmania infantum exerts immunomodulation in canine Kupffer cells reverted by meglumine antimoniate","volume":"55","author":"Rodrigues","year":"2017","journal-title":"Comp. Immunol. Microbiol. Infect. Dis."},{"key":"ref_16","first-page":"7","article-title":"Comparative study of infectivity caused by promastigotes of Leishmania infantum MON-1, L. infantum MON-24 and L. donovani MON-18","volume":"43","author":"Abranches","year":"1996","journal-title":"Folia Parasitol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.cimid.2015.03.003","article-title":"New insights into neutrophil and Leishmania infantum in vitro immune interactions","volume":"40","author":"Marques","year":"2015","journal-title":"Comp. Immunol. Microbiol. Infect. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.cellimm.2007.01.005","article-title":"H-2 complex influences cytokine gene expression in Leishmania infantum-infected macrophages","volume":"243","author":"Rodrigues","year":"2006","journal-title":"Cell Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/ni.3306","article-title":"Molecular control of activation and priming in macrophages","volume":"17","author":"Glass","year":"2016","journal-title":"Nat. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1038\/ni.2419","article-title":"Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages","volume":"13","author":"Gautiar","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1016\/j.cell.2014.11.018","article-title":"Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment","volume":"159","author":"Lavin","year":"2014","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1089\/ars.2016.6695","article-title":"Epigenetic Regulation of Monocyte and Macrophage Function","volume":"25","author":"Hoeksema","year":"2016","journal-title":"Antioxid. Redox Signal."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1038\/nm.4430","article-title":"Barrier-tissue macrophages: Functional adaptation to environmental challenges","volume":"23","author":"Mowat","year":"2017","journal-title":"Nat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.3389\/fimmu.2020.01066","article-title":"Phagocytosis: Our Current Understanding of a Universal Biological Process","volume":"11","author":"Rosales","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/tra.12026","article-title":"Presentation of Phagocytosed Antigens by MHC Class I and II","volume":"14","author":"Mantegazza","year":"2013","journal-title":"Traffic"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"111","DOI":"10.2217\/fmb.14.103","article-title":"Leishmania and the macrophage: A multifaceted interaction","volume":"10","author":"Podinovskaia","year":"2015","journal-title":"Future Microbiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1186\/s13071-016-1540-3","article-title":"The site of the bite: Leishmania interaction with macrophages, neutrophils and the extracellular matrix in the dermis","volume":"9","author":"Saraiva","year":"2016","journal-title":"Parasites Vectors"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Rogers, M., Kropf, P., Choi, B.S., Dillon, R., Podinovskaia, M., Bates, P., and M\u00fcller, I. (2009). Proteophosophoglycans regurgitated by Leishmania-infected sand flies target the L-arginine metabolism of host macrophages to promote parasite survival. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000555"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/j.micinf.2010.05.014","article-title":"Leishmania infantum proteophosphoglycans regurgitated by the bite of its natural sand fly vector, Lutzomyia longipalpis, promote parasite establishment in mouse skin and skin-distant tissues","volume":"12","author":"Rogers","year":"2010","journal-title":"Microb. Infect."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Poulaki, A., Piperaki, E.T., and Voulgarelis, M. (2021). Effects of visceralising Leishmania on the spleen, liver, and bone marrow: A pathophysiological perspective. Microorganisms, 9.","DOI":"10.3390\/microorganisms9040759"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jaut.2009.08.008","article-title":"Immune tolerance: What is unique about the liver","volume":"34","author":"Tiegs","year":"2010","journal-title":"J. Autoimmun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1017\/S0031182018002068","article-title":"Dog hepatocytes are key effector cells in the liver innate immune response to Leishmania infantum","volume":"146","author":"Rodrigues","year":"2019","journal-title":"Parasitology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3704","DOI":"10.1128\/IAI.01862-14","article-title":"Expression of regulatory T cells in jejunum, colon, and cervical and mesenteric lymph nodes of dogs naturally infected with Leishmania infantum","volume":"82","author":"Figueiredo","year":"2014","journal-title":"Infect. Immun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1017\/S003118201600055X","article-title":"Insights on adaptive and innate immunity in canine leishmaniosis","volume":"144","author":"Hosein","year":"2017","journal-title":"Parasitology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.vetimm.2014.11.010","article-title":"Transcription of innate immunity genes and cytokine secretion by canine macrophages resistant or susceptible to intracellular survival of Leishmania infantum","volume":"163","author":"Turchetti","year":"2015","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"618","DOI":"10.4269\/ajtmh.2004.70.618","article-title":"Organ-specific immunity in canine visceral leishmaniasis: Analysis of symptomatic and asymptomatic dogs naturally infected with Leishmania chagasi","volume":"70","author":"Sanchez","year":"2004","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1111\/j.1365-2613.2009.00681.x","article-title":"Hepatic extracellular matrix alterations in dogs naturally infected with Leishmania (Leishmania) chagasi","volume":"90","author":"Tafuri","year":"2009","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_38","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_39","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1189\/jlb.72.1.101","article-title":"A novel phenotype for an activated macrophage: The type 2 activated macrophage","volume":"72","author":"Anderson","year":"2002","journal-title":"J. Leukoc. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.vetpar.2016.06.032","article-title":"Polarized M2 macrophages in dogs with visceral leishmaniasis","volume":"226","author":"Moreira","year":"2016","journal-title":"Vet. Parasitol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1159\/000480373","article-title":"Macrophage Extracellular Traps: A Scoping Review","volume":"10","author":"Doster","year":"2018","journal-title":"J. Innate Immun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1126\/science.1092385","article-title":"Neutrophil Extracellular Traps Kill Bacteria","volume":"303","author":"Brinkmann","year":"2004","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1083\/jcb.200606027","article-title":"Novel cell death program leads to neutrophil extracellular traps","volume":"176","author":"Fuchs","year":"2007","journal-title":"J. Cell Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6748","DOI":"10.1073\/pnas.0900226106","article-title":"Leishmania amazonensis promastigotes induce and are killed by neutrophil extracellular traps","volume":"106","author":"Nascimento","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.cellimm.2018.11.003","article-title":"Intracellular and extracellular effector activity of mouse neutrophils in response to cutaneous and visceral Leishmania parasites","volume":"335","author":"Pereira","year":"2019","journal-title":"Cell Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/pim.12078","article-title":"Neutrophils have a protective role during early stages of Leishmania amazonensis infection in BALB\/c mice","volume":"36","author":"Sousa","year":"2014","journal-title":"Parasite Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6706","DOI":"10.4049\/jimmunol.171.12.6706","article-title":"at the Single-Cell Level Macrophage Antigen Presentation Analyzed-Induced Inhibition of Leishmania","volume":"171","author":"Meier","year":"2003","journal-title":"J. Immunol. Ref."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1038\/sj.icb7100011","article-title":"Balancing immunity and pathology in visceral leishmaniasis","volume":"85","author":"Stanley","year":"2007","journal-title":"Immunol. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Rodrigues, A.V., Alexandre-Pires, G., Val\u00e9rio-Bolas, A., Santos-Mateus, D., Rafael-Fernandes, M., Pereira, M.A., Ligeiro, D., Nunes, T., Alves-Azevedo, R., and Santos, M. (2020). 3D-hepatocyte culture applied to parasitology: Immune activation of canine hepatic spheroids exposed to Leishmania infantum. Biomedicines, 8.","DOI":"10.3390\/biomedicines8120628"}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/11\/1\/100\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:27:06Z","timestamp":1760362026000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/11\/1\/100"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,9]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["biology11010100"],"URL":"https:\/\/doi.org\/10.3390\/biology11010100","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,9]]}}}