{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T16:15:35Z","timestamp":1792080935984,"version":"4.4.0"},"update-to":[{"DOI":"10.1371\/journal.pntd.0009622","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,8,3]],"date-time":"2021-08-03T00:00:00Z","timestamp":1627948800000}}],"reference-count":81,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T00:00:00Z","timestamp":1626912000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["1136417N"],"award-info":[{"award-number":["1136417N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["12I0317N"],"award-info":[{"award-number":["12I0317N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007660","name":"Universiteit Antwerpen","doi-asserted-by":"publisher","award":["TT-ZAPBOF 33049"],"award-info":[{"award-number":["TT-ZAPBOF 33049"]}],"id":[{"id":"10.13039\/501100007660","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007660","name":"Universiteit Antwerpen","doi-asserted-by":"publisher","award":["TOP-BOF 35017"],"award-info":[{"award-number":["TOP-BOF 35017"]}],"id":[{"id":"10.13039\/501100007660","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007660","name":"Universiteit Antwerpen","doi-asserted-by":"publisher","award":["TOP-BOF 35017"],"award-info":[{"award-number":["TOP-BOF 35017"]}],"id":[{"id":"10.13039\/501100007660","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Miltefosine (MIL) is currently the only oral drug available to treat visceral leishmaniasis but its use as first-line monotherapy has been compromised by an increasing treatment failure. Despite the scarce number of resistant clinical isolates, MIL-resistance by mutations in a single aminophospholipid transporter gene can easily be selected in a laboratory environment. These mutations result in a reduced survival in the mammalian host, which can partially be restored by exposure to MIL, suggesting a kind of drug-dependency.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methodology\/Principal findings<\/jats:title>\n                    <jats:p>\n                      To enable a combined study of the infection dynamics and underlying immunological events for differential\n                      <jats:italic>in vivo<\/jats:italic>\n                      survival, firefly luciferase (PpyRE9) \/ red fluorescent protein (DsRed) double-reporter strains were generated of MIL-resistant (MIL-R) and syngeneic MIL-sensitive (MIL-S)\n                      <jats:italic>Leishmania infantum<\/jats:italic>\n                      . Results in C57Bl\/6 and BALB\/c mice show that MIL-R parasites induce an increased innate immune response that is characterized by enhanced influx and infection of neutrophils, monocytes and dendritic cells in the liver and elevated serum IFN-\u03b3 levels, finally resulting in a less efficient establishment in liver macrophages. The elevated IFN-\u03b3 levels were shown to originate from an increased response of hepatic NK and NKT cells to the MIL-R parasites. In addition, we demonstrated that MIL could increase the\n                      <jats:italic>in vivo<\/jats:italic>\n                      fitness of MIL-R parasites by lowering NK and NKT cell activation, leading to a reduced IFN-\u03b3 production.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusions\/Significance<\/jats:title>\n                    <jats:p>Differential induction of innate immune responses in the liver was found to underlie the attenuated phenotype of a MIL-R parasite and its peculiar feature of drug-dependency. The impact of MIL on hepatic NK and NKT activation and IFN-\u03b3 production following recognition of a MIL-R strain indicates that this mechanism may sustain infections with resistant parasites and contribute to treatment failure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pntd.0009622","type":"journal-article","created":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T13:55:07Z","timestamp":1626962107000},"page":"e0009622","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":20,"title":["Miltefosine enhances infectivity of a miltefosine-resistant Leishmania infantum strain by attenuating its innate immune recognition"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2783-4860","authenticated-orcid":true,"given":"Dimitri","family":"Bult\u00e9","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8882-8261","authenticated-orcid":true,"given":"Lieselotte","family":"Van Bockstal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1020-466X","authenticated-orcid":true,"given":"Laura","family":"Dirkx","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magali","family":"Van den Kerkhof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl","family":"De Trez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2506-6252","authenticated-orcid":true,"given":"Jean-Pierre","family":"Timmermans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Hendrickx","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2324-9509","authenticated-orcid":true,"given":"Louis","family":"Maes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4870-3202","authenticated-orcid":true,"given":"Guy","family":"Caljon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,7,22]]},"reference":[{"key":"pntd.0009622.ref001","doi-asserted-by":"crossref","first-page":"147","DOI":"10.2147\/CLEP.S44267","article-title":"Epidemiology of visceral leishmaniasis","volume":"6","author":"PD Ready","year":"2014","journal-title":"Clin Epidemiol."},{"key":"pntd.0009622.ref002","doi-asserted-by":"crossref","first-page":"e02851","DOI":"10.7554\/eLife.02851","article-title":"Global distribution maps of the leishmaniases","volume":"3","author":"DM Pigott","year":"2014","journal-title":"Elife"},{"issue":"2","key":"pntd.0009622.ref003","first-page":"399","article-title":"Leishmaniasis emergence and climate change","volume":"27","author":"PD Ready","year":"2008","journal-title":"Rev. sci. tech. off. int. 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