A chronic bioluminescent model of experimental visceral leishmaniasis for accelerating drug discovery.
Animals
Antiprotozoal Agents
/ pharmacology
Disease Models, Animal
Drug Discovery
/ methods
Female
Leishmania infantum
/ drug effects
Leishmaniasis, Visceral
/ diagnostic imaging
Luminescent Measurements
Luminescent Proteins
/ genetics
Mice
Mice, Inbred BALB C
Phosphorylcholine
/ analogs & derivatives
Spleen
/ parasitology
Journal
PLoS neglected tropical diseases
ISSN: 1935-2735
Titre abrégé: PLoS Negl Trop Dis
Pays: United States
ID NLM: 101291488
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
22
06
2018
accepted:
06
01
2019
revised:
27
02
2019
pubmed:
15
2
2019
medline:
21
3
2019
entrez:
15
2
2019
Statut:
epublish
Résumé
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. 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. 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.
Sections du résumé
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.
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.
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.
Identifiants
pubmed: 30763330
doi: 10.1371/journal.pntd.0007133
pii: PNTD-D-18-00984
pmc: PMC6392311
doi:
Substances chimiques
Antiprotozoal Agents
0
Luminescent Proteins
0
Phosphorylcholine
107-73-3
miltefosine
53EY29W7EC
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0007133Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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