Fitness and phenotypic characterization of miltefosine-resistant Leishmania major

Autores
Turner, Kimbra G.; Vacchina, Paola; Robles Murguia, Maricela; Wadsworth, Mariha; McDowell, Mary Ann; Morales, Miguel A.
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Trypanosomatid parasites of the genus Leishmania are the causative agents of leishmaniasis, a neglected tropical disease with several clinical manifestations. Leishmania major is the causative agent of cutaneous leishmaniasis (CL), which is largely characterized by ulcerative lesions appearing on the skin. Current treatments of leishmaniasis include pentavalent antimonials and amphotericin B, however, the toxic side effects of these drugs and difficulty with distribution makes these options less than ideal. Miltefosine (MIL) is the first oral treatment available for leishmaniasis. Originally developed for cancer chemotherapy, the mechanism of action of MIL in Leishmania spp. is largely unknown. While treatment with MIL has proven effective, higher tolerance to the drug has been observed, and resistance is easily developed in an in vitro environment. Utilizing stepwise selection we generated MIL-resistant cultures of L. major and characterized the fitness of MIL-resistant L. major. Resistant parasites proliferate at a comparable rate to the wild-type (WT) and exhibit similar apoptotic responses. As expected, MIL-resistant parasites demonstrate decreased susceptibility to MIL, which reduces after the drug is withdrawn from culture. Our data demonstrate metacyclogenesis is elevated in MIL-resistant L. major, albeit these parasites display attenuated in vitro and in vivo virulence and standard survival rates in the natural sandfly vector, indicating that development of experimental resistance to miltefosine does not lead to an increased competitive fitness in L. major.
Fil: Turner, Kimbra G.. University of Notre Dame-Indiana; Estados Unidos
Fil: Vacchina, Paola. University of Notre Dame-Indiana; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Robles Murguia, Maricela. University of Notre Dame-Indiana; Estados Unidos
Fil: Wadsworth, Mariha. University of Notre Dame-Indiana; Estados Unidos
Fil: McDowell, Mary Ann. University of Notre Dame-Indiana; Estados Unidos
Fil: Morales, Miguel A.. University of Notre Dame-Indiana; Estados Unidos
Materia
LEISHMANIA MAJOR
MILTEFOSINE RESISTANCE
PARASITE FITNESS
SAND FLIES
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/52400
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Fitness and phenotypic characterization of miltefosine-resistant Leishmania majorTurner, Kimbra G.Vacchina, PaolaRobles Murguia, MaricelaWadsworth, MarihaMcDowell, Mary AnnMorales, Miguel A.LEISHMANIA MAJORMILTEFOSINE RESISTANCEPARASITE FITNESSSAND FLIEShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Trypanosomatid parasites of the genus Leishmania are the causative agents of leishmaniasis, a neglected tropical disease with several clinical manifestations. Leishmania major is the causative agent of cutaneous leishmaniasis (CL), which is largely characterized by ulcerative lesions appearing on the skin. Current treatments of leishmaniasis include pentavalent antimonials and amphotericin B, however, the toxic side effects of these drugs and difficulty with distribution makes these options less than ideal. Miltefosine (MIL) is the first oral treatment available for leishmaniasis. Originally developed for cancer chemotherapy, the mechanism of action of MIL in Leishmania spp. is largely unknown. While treatment with MIL has proven effective, higher tolerance to the drug has been observed, and resistance is easily developed in an in vitro environment. Utilizing stepwise selection we generated MIL-resistant cultures of L. major and characterized the fitness of MIL-resistant L. major. Resistant parasites proliferate at a comparable rate to the wild-type (WT) and exhibit similar apoptotic responses. As expected, MIL-resistant parasites demonstrate decreased susceptibility to MIL, which reduces after the drug is withdrawn from culture. Our data demonstrate metacyclogenesis is elevated in MIL-resistant L. major, albeit these parasites display attenuated in vitro and in vivo virulence and standard survival rates in the natural sandfly vector, indicating that development of experimental resistance to miltefosine does not lead to an increased competitive fitness in L. major.Fil: Turner, Kimbra G.. University of Notre Dame-Indiana; Estados UnidosFil: Vacchina, Paola. University of Notre Dame-Indiana; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Robles Murguia, Maricela. University of Notre Dame-Indiana; Estados UnidosFil: Wadsworth, Mariha. University of Notre Dame-Indiana; Estados UnidosFil: McDowell, Mary Ann. University of Notre Dame-Indiana; Estados UnidosFil: Morales, Miguel A.. University of Notre Dame-Indiana; Estados UnidosPublic Library of Science2015-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/52400Turner, Kimbra G.; Vacchina, Paola; Robles Murguia, Maricela; Wadsworth, Mariha; McDowell, Mary Ann; et al.; Fitness and phenotypic characterization of miltefosine-resistant Leishmania major; Public Library of Science; Neglected Tropical Diseases; 9; 7; 7-2015; 1-15; e00039481935-2735CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pntd.0003948info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0003948info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:06:04Zoai:ri.conicet.gov.ar:11336/52400instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:06:05.173CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Fitness and phenotypic characterization of miltefosine-resistant Leishmania major
title Fitness and phenotypic characterization of miltefosine-resistant Leishmania major
spellingShingle Fitness and phenotypic characterization of miltefosine-resistant Leishmania major
Turner, Kimbra G.
LEISHMANIA MAJOR
MILTEFOSINE RESISTANCE
PARASITE FITNESS
SAND FLIES
title_short Fitness and phenotypic characterization of miltefosine-resistant Leishmania major
title_full Fitness and phenotypic characterization of miltefosine-resistant Leishmania major
title_fullStr Fitness and phenotypic characterization of miltefosine-resistant Leishmania major
title_full_unstemmed Fitness and phenotypic characterization of miltefosine-resistant Leishmania major
title_sort Fitness and phenotypic characterization of miltefosine-resistant Leishmania major
dc.creator.none.fl_str_mv Turner, Kimbra G.
Vacchina, Paola
Robles Murguia, Maricela
Wadsworth, Mariha
McDowell, Mary Ann
Morales, Miguel A.
author Turner, Kimbra G.
author_facet Turner, Kimbra G.
Vacchina, Paola
Robles Murguia, Maricela
Wadsworth, Mariha
McDowell, Mary Ann
Morales, Miguel A.
author_role author
author2 Vacchina, Paola
Robles Murguia, Maricela
Wadsworth, Mariha
McDowell, Mary Ann
Morales, Miguel A.
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv LEISHMANIA MAJOR
MILTEFOSINE RESISTANCE
PARASITE FITNESS
SAND FLIES
topic LEISHMANIA MAJOR
MILTEFOSINE RESISTANCE
PARASITE FITNESS
SAND FLIES
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Trypanosomatid parasites of the genus Leishmania are the causative agents of leishmaniasis, a neglected tropical disease with several clinical manifestations. Leishmania major is the causative agent of cutaneous leishmaniasis (CL), which is largely characterized by ulcerative lesions appearing on the skin. Current treatments of leishmaniasis include pentavalent antimonials and amphotericin B, however, the toxic side effects of these drugs and difficulty with distribution makes these options less than ideal. Miltefosine (MIL) is the first oral treatment available for leishmaniasis. Originally developed for cancer chemotherapy, the mechanism of action of MIL in Leishmania spp. is largely unknown. While treatment with MIL has proven effective, higher tolerance to the drug has been observed, and resistance is easily developed in an in vitro environment. Utilizing stepwise selection we generated MIL-resistant cultures of L. major and characterized the fitness of MIL-resistant L. major. Resistant parasites proliferate at a comparable rate to the wild-type (WT) and exhibit similar apoptotic responses. As expected, MIL-resistant parasites demonstrate decreased susceptibility to MIL, which reduces after the drug is withdrawn from culture. Our data demonstrate metacyclogenesis is elevated in MIL-resistant L. major, albeit these parasites display attenuated in vitro and in vivo virulence and standard survival rates in the natural sandfly vector, indicating that development of experimental resistance to miltefosine does not lead to an increased competitive fitness in L. major.
Fil: Turner, Kimbra G.. University of Notre Dame-Indiana; Estados Unidos
Fil: Vacchina, Paola. University of Notre Dame-Indiana; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Robles Murguia, Maricela. University of Notre Dame-Indiana; Estados Unidos
Fil: Wadsworth, Mariha. University of Notre Dame-Indiana; Estados Unidos
Fil: McDowell, Mary Ann. University of Notre Dame-Indiana; Estados Unidos
Fil: Morales, Miguel A.. University of Notre Dame-Indiana; Estados Unidos
description Trypanosomatid parasites of the genus Leishmania are the causative agents of leishmaniasis, a neglected tropical disease with several clinical manifestations. Leishmania major is the causative agent of cutaneous leishmaniasis (CL), which is largely characterized by ulcerative lesions appearing on the skin. Current treatments of leishmaniasis include pentavalent antimonials and amphotericin B, however, the toxic side effects of these drugs and difficulty with distribution makes these options less than ideal. Miltefosine (MIL) is the first oral treatment available for leishmaniasis. Originally developed for cancer chemotherapy, the mechanism of action of MIL in Leishmania spp. is largely unknown. While treatment with MIL has proven effective, higher tolerance to the drug has been observed, and resistance is easily developed in an in vitro environment. Utilizing stepwise selection we generated MIL-resistant cultures of L. major and characterized the fitness of MIL-resistant L. major. Resistant parasites proliferate at a comparable rate to the wild-type (WT) and exhibit similar apoptotic responses. As expected, MIL-resistant parasites demonstrate decreased susceptibility to MIL, which reduces after the drug is withdrawn from culture. Our data demonstrate metacyclogenesis is elevated in MIL-resistant L. major, albeit these parasites display attenuated in vitro and in vivo virulence and standard survival rates in the natural sandfly vector, indicating that development of experimental resistance to miltefosine does not lead to an increased competitive fitness in L. major.
publishDate 2015
dc.date.none.fl_str_mv 2015-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/52400
Turner, Kimbra G.; Vacchina, Paola; Robles Murguia, Maricela; Wadsworth, Mariha; McDowell, Mary Ann; et al.; Fitness and phenotypic characterization of miltefosine-resistant Leishmania major; Public Library of Science; Neglected Tropical Diseases; 9; 7; 7-2015; 1-15; e0003948
1935-2735
CONICET Digital
CONICET
url http://hdl.handle.net/11336/52400
identifier_str_mv Turner, Kimbra G.; Vacchina, Paola; Robles Murguia, Maricela; Wadsworth, Mariha; McDowell, Mary Ann; et al.; Fitness and phenotypic characterization of miltefosine-resistant Leishmania major; Public Library of Science; Neglected Tropical Diseases; 9; 7; 7-2015; 1-15; e0003948
1935-2735
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pntd.0003948
info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0003948
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
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:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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