ArticlePLoS neglected tropical diseases2021
Miltefosine enhances infectivity of a miltefosine-resistant Leishmania infantum strain by attenuating its innate immune recognition.
Article in PLoS neglected tropical diseases, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 21 citations in OpenAlex.
- Baseline of miltefosine resistance markers in zoonoticOne health (Amsterdam, Netherlands) · 2026Article
- Miltefosine and emerging Leishmania (Mundinia) in Southeast Asia: Molecular insights, therapeutic challenges, and future strategic implementation.PLoS neglected tropical diseases · 2026Review
- Persistent myeloid cell reprogramming despite miltefosine treatment in leishmania-infected macaques.iScience · 2025Article
- Article
- The different impact of drug-resistantiScience · 2024Article
- Long-term hematopoietic stem cells trigger quiescence in Leishmania parasites.PLoS pathogens · 2024Article
- Unmasking the Mechanism behind Miltefosine: Revealing the Disruption of Intracellular CaBiomolecules · 2024Review
- Construction of luciferase-expressing Neospora caninum and drug screening.Parasites & vectors · 2024Article
- Factors associated with survival in patients with visceral leishmaniasis treated at a reference hospital in northern Minas Gerais - Brazil.Revista da Sociedade Brasileira de Medicina Tropical · 2024Article
- The Therapeutic Effects of Curcumin-coated Gold Nanoparticle Against Leishmania Major Causative Agent of Zoonotic Cutaneous Leishmaniasis (ZCL): An In Vitro and In Vivo Study.Current microbiology · 2023Article
- Comparison of Bioluminescent Substrates in Natural Infection Models of Neglected Parasitic Diseases.International journal of molecular sciences · 2022Article
- Impact of pulmonary African trypanosomes on the immunology and function of the lung.Nature communications · 2022Article
- Development of Novel Anti-Leishmanials: The Case for Structure-Based Approaches.Pathogens (Basel, Switzerland) · 2022Review
- Long-term hematopoietic stem cells as a parasite niche during treatment failure in visceral leishmaniasis.Communications biology · 2022Article
- In-Depth Quantitative Proteomics Characterization of In Vitro Selected Miltefosine Resistance inProteomes · 2022Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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/SIGNIFICANCE: 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.
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