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A chronic bioluminescent model of experimental visceral leishmaniasis for accelerating drug discovery.
- Source :
-
PLoS neglected tropical diseases [PLoS Negl Trop Dis] 2019 Feb 14; Vol. 13 (2), pp. e0007133. Date of Electronic Publication: 2019 Feb 14 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- Background: Visceral leishmaniasis is a neglected parasitic disease with no vaccine available and its pharmacological treatment is reduced to a limited number of unsafe drugs. The scarce readiness of new antileishmanial drugs is even more alarming when relapses appear or the occurrence of hard-to-treat resistant strains is detected. In addition, there is a gap between the initial and late stages of drug development, which greatly delays the selection of leads for subsequent studies.<br />Methodology/principal Findings: In order to address these issues, we have generated a red-shifted luminescent Leishmania infantum strain that enables long-term monitoring of parasite burden in individual animals with an in vivo limit of detection of 106 intracellular amastigotes 48 h postinfection. For this purpose, we have injected intravenously different infective doses (104-5x108) of metacyclic parasites in susceptible mouse models and the disease was monitored from initial times to 21 weeks postinfection. The emission of light from the target organs demonstrated the sequential parasite colonization of liver, spleen and bone marrow. When miltefosine was used as proof-of-concept, spleen weight parasite burden and bioluminescence values decreased significantly.<br />Conclusions: In vivo bioimaging using a red-shifted modified Leishmania infantum strain allows the appraisal of acute and chronic stage of infection, being a powerful tool for accelerating drug development against visceral leishmaniasis during both stages and helping to bridge the gap between early discovery process and subsequent drug development.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Animals
Disease Models, Animal
Female
Leishmaniasis, Visceral drug therapy
Luminescent Proteins genetics
Luminescent Proteins metabolism
Mice
Mice, Inbred BALB C
Phosphorylcholine pharmacology
Spleen parasitology
Antiprotozoal Agents pharmacology
Drug Discovery methods
Leishmania infantum drug effects
Leishmaniasis, Visceral diagnostic imaging
Luminescent Measurements
Phosphorylcholine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1935-2735
- Volume :
- 13
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- PLoS neglected tropical diseases
- Publication Type :
- Academic Journal
- Accession number :
- 30763330
- Full Text :
- https://doi.org/10.1371/journal.pntd.0007133