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Published on: October 28, 2022
Miltefosine resistance in Leishmania donovani involves suppression of oxidative stress-induced programmed cell death
1Division of Clinical Microbiology, All India Institute of Medical Sciences, New Delhi, India.
Abstract:
Miltefosine (MIL), an alkylphospholipid, is the first orally administrable anti-leishmanial drug. But due to its long half-life, miltefosine is highly vulnerable for resistance. Hence it is important to understand the mechanism of resistance and to elucidate its action on Leishmania. Here we investigate the miltefosine induced process of programmed cell death in wild type (miltefosine sensitive) and in laboratory generated resistant strains of Leishmania donovani. Results indicate that miltefosine induced apoptosis like death in a time and dose dependent manner in wild-type cells, but not in MIL-resistant cell line. The miltefosine resistant cells remained protected against miltefosine-induced loss of mitochondrial membrane potential, gradual ATP loss and cytochrome C release from mitochondria into the cytosol. Comparative transcriptomic study showed significantly increased expression of FeSODA and SIR2 genes, putatively involved in oxidative stress associated apoptotic cell death. We hypothesize that oxidative stress mediated apoptosis as an alternative mechanism of miltefosine resistance.
Insights
Miltefosine (MIL) causes apoptosis in Leishmania parasites, but resistant strains are protected. Increased FeSODA and SIR2 gene expression suggests oxidative stress may be an alternative resistance mechanism.
Area of Science:
- Parasitology
- Molecular Biology
- Drug Resistance
Background:
- Miltefosine (MIL) is an orally administered anti-leishmanial drug.
- MIL's long half-life contributes to drug resistance, necessitating understanding of its action and resistance mechanisms in Leishmania.
- Investigating programmed cell death pathways is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the mechanism of programmed cell death induced by miltefosine in Leishmania donovani.
- To compare the cellular response to miltefosine in drug-sensitive and drug-resistant Leishmania donovani strains.
- To identify potential molecular pathways involved in miltefosine resistance.
Main Methods:
- Induction of apoptosis-like death in wild-type and laboratory-generated miltefosine-resistant Leishmania donovani strains.
- Assessment of mitochondrial membrane potential, ATP levels, and cytochrome C release.
- Comparative transcriptomic analysis to identify differentially expressed genes.
Main Results:
- Miltefosine induced apoptosis-like cell death in a time- and dose-dependent manner in wild-type Leishmania donovani.
- Miltefosine-resistant cells were protected from MIL-induced apoptosis, showing preserved mitochondrial membrane potential, ATP levels, and no cytochrome C release.
- Transcriptomic analysis revealed significantly increased expression of FeSODA and SIR2 genes in resistant cells, suggesting a role in oxidative stress-mediated apoptosis.
Conclusions:
- Miltefosine triggers apoptosis in sensitive Leishmania donovani.
- Resistance to miltefosine involves protection against apoptosis, including maintaining mitochondrial function and preventing cytochrome C release.
- Oxidative stress, potentially mediated by FeSODA and SIR2 gene upregulation, is hypothesized as an alternative mechanism for miltefosine resistance in Leishmania.
