A chronic bioluminescent model of experimental visceral leishmaniasis for accelerating drug discovery

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-tre...

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Autores: Álvarez-Velilla, Raquel, Gutiérrez-Corbo, M. del Camino, Punzón, Carmen, Pérez-Pertejo, Yolanda, Balaña-Fouce, Rafael, Fresno, Manuel, Reguera, Rosa María
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/213145
Acceso en línea:http://hdl.handle.net/10261/213145
Access Level:acceso abierto
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spelling A chronic bioluminescent model of experimental visceral leishmaniasis for accelerating drug discoveryÁlvarez-Velilla, RaquelGutiérrez-Corbo, M. del CaminoPunzón, CarmenPérez-Pertejo, YolandaBalaña-Fouce, RafaelFresno, ManuelReguera, Rosa MaríaBackground 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 postinfecton. For thispurpose, 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 developmentConsejería de Educación de la Junta de Castilla y LeónPublic Library of ScienceJunta de Castilla y LeónConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020192020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/213145reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1371/journal.pntd.0007133Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2131452026-05-22T06:33:51Z
dc.title.none.fl_str_mv A chronic bioluminescent model of experimental visceral leishmaniasis for accelerating drug discovery
title A chronic bioluminescent model of experimental visceral leishmaniasis for accelerating drug discovery
spellingShingle A chronic bioluminescent model of experimental visceral leishmaniasis for accelerating drug discovery
Álvarez-Velilla, Raquel
title_short A chronic bioluminescent model of experimental visceral leishmaniasis for accelerating drug discovery
title_full A chronic bioluminescent model of experimental visceral leishmaniasis for accelerating drug discovery
title_fullStr A chronic bioluminescent model of experimental visceral leishmaniasis for accelerating drug discovery
title_full_unstemmed A chronic bioluminescent model of experimental visceral leishmaniasis for accelerating drug discovery
title_sort A chronic bioluminescent model of experimental visceral leishmaniasis for accelerating drug discovery
dc.creator.none.fl_str_mv Álvarez-Velilla, Raquel
Gutiérrez-Corbo, M. del Camino
Punzón, Carmen
Pérez-Pertejo, Yolanda
Balaña-Fouce, Rafael
Fresno, Manuel
Reguera, Rosa María
author Álvarez-Velilla, Raquel
author_facet Álvarez-Velilla, Raquel
Gutiérrez-Corbo, M. del Camino
Punzón, Carmen
Pérez-Pertejo, Yolanda
Balaña-Fouce, Rafael
Fresno, Manuel
Reguera, Rosa María
author_role author
author2 Gutiérrez-Corbo, M. del Camino
Punzón, Carmen
Pérez-Pertejo, Yolanda
Balaña-Fouce, Rafael
Fresno, Manuel
Reguera, Rosa María
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Junta de Castilla y León
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description 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 postinfecton. For thispurpose, 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
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/213145
url http://hdl.handle.net/10261/213145
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1371/journal.pntd.0007133
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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