Abstract
BackgroundMiltefosine (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.Methodology/Principal findingsTo 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.Conclusions/SignificanceDifferential 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.
Highlights
Visceral leishmaniasis (VL) is a fatal vector-borne disease that is caused by transmission of the protozoan parasite Leishmania donovani in Asia and parts of Africa and by L. infantum in the Mediterranean area and Latin America [1,2,3]
Miltefosine is currently the only oral drug available but is increasingly failing to cure patients, resulting in its discontinuation as first-line drug in some endemic areas. To understand these treatment failures, we investigated the complex interplay of the parasite with the host immune system in the presence and absence of miltefosine
Our data indicate that miltefosine-resistant Leishmania parasites become severely hampered in their in vivo infectivity, which could be attributed to the induction of a pronounced innate immune response
Summary
Visceral leishmaniasis (VL) is a fatal vector-borne disease that is caused by transmission of the protozoan parasite Leishmania donovani in Asia and parts of Africa and by L. infantum in the Mediterranean area and Latin America [1,2,3]. While several reports have shown that NK cells are not essential in shaping the early immune response, the absence of NKT cells or NKT cell activation result in decreased IFN-γ levels, PLOS NEGLECTED TROPICAL DISEASES Immune aspects of miltefosine resistance and drug-dependency in visceral leishmaniasis impaired granulomatous response and higher parasite burdens in both the liver and spleen [21,22]. Despite the scarce number of resistant clinical isolates, MIL-resistance by mutations in a single aminophospholipid transporter gene can 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
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