Miltefosine enhances infectivity of a miltefosine-resistant Leishmania infantum strain by attenuating its innate immune recognition.

<h4>Background</h4>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 mutati...

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Autores principales:	Dimitri Bulté, Lieselotte Van Bockstal, Laura Dirkx, Magali Van den Kerkhof, Carl De Trez, Jean-Pierre Timmermans, Sarah Hendrickx, Louis Maes, Guy Caljon
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/45bfdf7d1c8b4744b809bf929f0a57eb
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spelling	oai:doaj.org-article:45bfdf7d1c8b4744b809bf929f0a57eb2021-11-25T06:33:29ZMiltefosine enhances infectivity of a miltefosine-resistant Leishmania infantum strain by attenuating its innate immune recognition.1935-27271935-273510.1371/journal.pntd.0009622https://doaj.org/article/45bfdf7d1c8b4744b809bf929f0a57eb2021-07-01T00:00:00Zhttps://doi.org/10.1371/journal.pntd.0009622https://doaj.org/toc/1935-2727https://doaj.org/toc/1935-2735<h4>Background</h4>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.<h4>Methodology/principal findings</h4>To enable a combined study of the infection dynamics and underlying immunological events for differential in vivo survival, firefly luciferase (PpyRE9) / red fluorescent protein (DsRed) double-reporter strains were generated of MIL-resistant (MIL-R) and syngeneic MIL-sensitive (MIL-S) Leishmania infantum. 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-γ levels, finally resulting in a less efficient establishment in liver macrophages. The elevated IFN-γ 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 in vivo fitness of MIL-R parasites by lowering NK and NKT cell activation, leading to a reduced IFN-γ production.<h4>Conclusions/significance</h4>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-γ production following recognition of a MIL-R strain indicates that this mechanism may sustain infections with resistant parasites and contribute to treatment failure.Dimitri BultéLieselotte Van BockstalLaura DirkxMagali Van den KerkhofCarl De TrezJean-Pierre TimmermansSarah HendrickxLouis MaesGuy CaljonPublic Library of Science (PLoS)articleArctic medicine. Tropical medicineRC955-962Public aspects of medicineRA1-1270ENPLoS Neglected Tropical Diseases, Vol 15, Iss 7, p e0009622 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
spellingShingle	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Dimitri Bulté Lieselotte Van Bockstal Laura Dirkx Magali Van den Kerkhof Carl De Trez Jean-Pierre Timmermans Sarah Hendrickx Louis Maes Guy Caljon Miltefosine enhances infectivity of a miltefosine-resistant Leishmania infantum strain by attenuating its innate immune recognition.
description	<h4>Background</h4>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.<h4>Methodology/principal findings</h4>To enable a combined study of the infection dynamics and underlying immunological events for differential in vivo survival, firefly luciferase (PpyRE9) / red fluorescent protein (DsRed) double-reporter strains were generated of MIL-resistant (MIL-R) and syngeneic MIL-sensitive (MIL-S) Leishmania infantum. 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-γ levels, finally resulting in a less efficient establishment in liver macrophages. The elevated IFN-γ 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 in vivo fitness of MIL-R parasites by lowering NK and NKT cell activation, leading to a reduced IFN-γ production.<h4>Conclusions/significance</h4>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-γ production following recognition of a MIL-R strain indicates that this mechanism may sustain infections with resistant parasites and contribute to treatment failure.
format	article
author	Dimitri Bulté Lieselotte Van Bockstal Laura Dirkx Magali Van den Kerkhof Carl De Trez Jean-Pierre Timmermans Sarah Hendrickx Louis Maes Guy Caljon
author_facet	Dimitri Bulté Lieselotte Van Bockstal Laura Dirkx Magali Van den Kerkhof Carl De Trez Jean-Pierre Timmermans Sarah Hendrickx Louis Maes Guy Caljon
author_sort	Dimitri Bulté
title	Miltefosine enhances infectivity of a miltefosine-resistant Leishmania infantum strain by attenuating its innate immune recognition.
title_short	Miltefosine enhances infectivity of a miltefosine-resistant Leishmania infantum strain by attenuating its innate immune recognition.
title_full	Miltefosine enhances infectivity of a miltefosine-resistant Leishmania infantum strain by attenuating its innate immune recognition.
title_fullStr	Miltefosine enhances infectivity of a miltefosine-resistant Leishmania infantum strain by attenuating its innate immune recognition.
title_full_unstemmed	Miltefosine enhances infectivity of a miltefosine-resistant Leishmania infantum strain by attenuating its innate immune recognition.
title_sort	miltefosine enhances infectivity of a miltefosine-resistant leishmania infantum strain by attenuating its innate immune recognition.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/45bfdf7d1c8b4744b809bf929f0a57eb
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Miltefosine enhances infectivity of a miltefosine-resistant Leishmania infantum strain by attenuating its innate immune recognition.

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