Glutamine supplementation improves the efficacy of miltefosine treatment for visceral leishmaniasis
Open accessAbstract
BACKGROUND: The disturbance of host metabolic pathways by Leishmania parasites has crucial consequences for the activation status of immune cells and the outcome of infection. Glutamine has been described as an immunomodulatory amino acid, yet its role during Leishmania infection is still unknown. METHODS: We performed transcriptomics in uninfected and L. donovani-infected macrophages 6 hours post-infection. Glutamine quantification by HPLC was assessed in the supernatant of macrophages throughout the infection course. For experimental L. donovani infections, mice were infected with 1.0 x 108 stationary L. donovani promastigotes. Glutaminase (GLS) chemical inhibition was performed using BPTES and glutamine was administered throughout infection. For combined therapy experiment, a daily administration of miltefosine and glutamine was performed by oral gavage. Parasite burden was determined using a Taqman-based assay. Immune cell phenotyping and cytotoxicity were performed in splenic cells using flow cytometry. FINDINGS: We show that glutamine is essential for the control of L. donovani infection. Transcriptomic analysis of L. donovani-infected macrophages demonstrated an upregulation of genes involved in glutamine metabolism. Pharmacological inhibition of glutaminolysis significantly increased the susceptibility to infection, accompanied by an increased recruitment of anti-inflammatory myeloid cells and impaired T cell responses. Remarkably, the supplementation of glutamine to mice infected with L. donovani during miltefosine treatment potentiates parasite clearance through the development of a more effective anti-Leishmania adaptive immune response. CONCLUSIONS: Our data indicates that dietary glutamine supplementation may act as a promising adjuvant for the treatment of visceral leishmaniasis.
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Glutamine supplementation can offer a therapeutic approach for critical illnesses.
“Under these conditions, several studies have reported that glutamine supplementation can offer a therapeutic approach for these critical illnesses145–147.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [145]
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- Authors
- Ferreira, C., Mesquita, I., Barbosa, A. M., Osório, N. S., Torrado, E., Beauparlant, C.-J., Droit, A., Cunha, C., Carvalho, A., Saha, B., Estaquier, J., & Silvestre, R.
- Affiliations
- University of Minho (PT)
- Université Laval (CA)
- National Centre for Cell Science (IN)
- Corresponding author
- Silvestre, Ricardo
- ORCID
- Venue
- PLOS Neglected Tropical Diseases
- Publisher
- Public Library of Science (PLoS)
- Published
- 2020-03-26
- Volume
- 14
- Issue
- 3
- Pages
- e0008125
- ISSN
- 1935-2727 (ISSN-L)
- 1935-2735
- PMC
- PMC7138311
- OpenAlex
- W3013566561
- Cited by
- 35
- References
- 46
- Citations by year
- 2025: 1 · 2024: 4 · 2023: 14 · 2022: 6 · 2021: 6 · 2020: 4
- FWCI
- 6.00
- Type
- journal article
- Language
- en
- Update notices
- new_version (2020-04-07)
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS neglected tropical diseases (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Fundação para a Ciência e a Tecnologia (PD/BDE/127830/2016, SFRH/BD/120127/2016, SFRH/BD/120371/2016, IF/00474/2014, IF/01390/2014, CEECIND/03628/2017, CEECIND/04600/2017, IF/00021/2014)
- Horizon 2020 Framework Programme (INLEISH)
- Canada Research Chairs
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Research on Leishmaniasis Studies
- Health Sciences › Medicine › Infectious Diseases › Leprosy Research and Treatment
- Health Sciences › Medicine › Epidemiology › Trypanosoma species research and implications
- Keywords
- glutamine supplementation, miltefosine, visceral leishmaniasis, Leishmania donovani, glutamine metabolism, glutaminase inhibition, BPTES, macrophages, parasite clearance, T cell response, myeloid cell recruitment, adjuvant therapy, host-parasite metabolic interactions
- MeSH terms
- Animals, Antiprotozoal Agents, Disease Models, Animal, Female, Glutamine, Humans, Immunologic Factors, Leishmaniasis, Visceral, Macrophages, Male, Mice, Inbred C57BL, Phosphorylcholine, T-Lymphocyte Subsets, Treatment Outcome, Dietary Supplements, Parasite Load
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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