Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection
Abstract Background Since the introduction of miltefosine (MIL) as first-line therapy in the kala-azar elimination programme in the Indian subcontinent, treatment failure rates have been increasing. Since parasite infectivity and virulence may become altered upon treatment relapse, this laboratory s...
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| Format: | Article |
| Language: | English |
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BMC
2020-02-01
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| Series: | Parasites & Vectors |
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| Online Access: | http://link.springer.com/article/10.1186/s13071-020-3972-z |
| _version_ | 1818879624339259392 |
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| author | Sarah Hendrickx Lieselotte Van Bockstal Dimitri Bulté Annelies Mondelaers Hamide Aslan Luis Rivas Louis Maes Guy Caljon |
| author_facet | Sarah Hendrickx Lieselotte Van Bockstal Dimitri Bulté Annelies Mondelaers Hamide Aslan Luis Rivas Louis Maes Guy Caljon |
| author_sort | Sarah Hendrickx |
| collection | DOAJ |
| description | Abstract Background Since the introduction of miltefosine (MIL) as first-line therapy in the kala-azar elimination programme in the Indian subcontinent, treatment failure rates have been increasing. Since parasite infectivity and virulence may become altered upon treatment relapse, this laboratory study assessed the phenotypic effects of repeated in vitro and in vivo MIL exposure. Methods Syngeneic Leishmania donovani lines either or not exposed to MIL were compared for drug susceptibility, rate of promastigote multiplication and metacyclogenesis, macrophage infectivity and behaviour in the sand fly vector, Lutzomyia longipalpis. Results Promastigotes of both in vitro and in vivo MIL-selected strains displayed a slightly reduced drug susceptibility that was associated with a reduced MIL-accumulation linked to a lower copy number (disomic state) of chromosome 13 harboring the miltefosine transporter (LdMT) gene. In vitro selected promastigotes showed a lower rate of metacyclogenesis whereas the in vivo derived promastigotes displayed a moderately increased growth rate. Repeated MIL exposure did neither influence the parasite load nor metacyclogenesis in the sand fly vector. Conclusions Recurrent in vitro and in vivo MIL exposure evokes a number of very subtle phenotypic and genotypic changes which could make promastigotes less susceptible to MIL without attaining full resistance. These changes did not significantly impact on infection in the sand fly vector. |
| first_indexed | 2024-12-19T14:33:02Z |
| format | Article |
| id | doaj.art-7014af4ac7cf4b78908c0dff4a925fd3 |
| institution | Directory Open Access Journal |
| issn | 1756-3305 |
| language | English |
| last_indexed | 2024-12-19T14:33:02Z |
| publishDate | 2020-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Parasites & Vectors |
| spelling | doaj.art-7014af4ac7cf4b78908c0dff4a925fd32022-12-21T20:17:23ZengBMCParasites & Vectors1756-33052020-02-0113111110.1186/s13071-020-3972-zPhenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infectionSarah Hendrickx0Lieselotte Van Bockstal1Dimitri Bulté2Annelies Mondelaers3Hamide Aslan4Luis Rivas5Louis Maes6Guy Caljon7Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of AntwerpLaboratory of Microbiology, Parasitology and Hygiene (LMPH), University of AntwerpLaboratory of Microbiology, Parasitology and Hygiene (LMPH), University of AntwerpLaboratory of Microbiology, Parasitology and Hygiene (LMPH), University of AntwerpLaboratory of Microbiology, Parasitology and Hygiene (LMPH), University of AntwerpCentro de investigaciones Biológicas - CSICLaboratory of Microbiology, Parasitology and Hygiene (LMPH), University of AntwerpLaboratory of Microbiology, Parasitology and Hygiene (LMPH), University of AntwerpAbstract Background Since the introduction of miltefosine (MIL) as first-line therapy in the kala-azar elimination programme in the Indian subcontinent, treatment failure rates have been increasing. Since parasite infectivity and virulence may become altered upon treatment relapse, this laboratory study assessed the phenotypic effects of repeated in vitro and in vivo MIL exposure. Methods Syngeneic Leishmania donovani lines either or not exposed to MIL were compared for drug susceptibility, rate of promastigote multiplication and metacyclogenesis, macrophage infectivity and behaviour in the sand fly vector, Lutzomyia longipalpis. Results Promastigotes of both in vitro and in vivo MIL-selected strains displayed a slightly reduced drug susceptibility that was associated with a reduced MIL-accumulation linked to a lower copy number (disomic state) of chromosome 13 harboring the miltefosine transporter (LdMT) gene. In vitro selected promastigotes showed a lower rate of metacyclogenesis whereas the in vivo derived promastigotes displayed a moderately increased growth rate. Repeated MIL exposure did neither influence the parasite load nor metacyclogenesis in the sand fly vector. Conclusions Recurrent in vitro and in vivo MIL exposure evokes a number of very subtle phenotypic and genotypic changes which could make promastigotes less susceptible to MIL without attaining full resistance. These changes did not significantly impact on infection in the sand fly vector.http://link.springer.com/article/10.1186/s13071-020-3972-zMiltefosineLeishmaniaFitnessLutzomyia longipalpisDrug uptake |
| spellingShingle | Sarah Hendrickx Lieselotte Van Bockstal Dimitri Bulté Annelies Mondelaers Hamide Aslan Luis Rivas Louis Maes Guy Caljon Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection Parasites & Vectors Miltefosine Leishmania Fitness Lutzomyia longipalpis Drug uptake |
| title | Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection |
| title_full | Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection |
| title_fullStr | Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection |
| title_full_unstemmed | Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection |
| title_short | Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection |
| title_sort | phenotypic adaptations of leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection |
| topic | Miltefosine Leishmania Fitness Lutzomyia longipalpis Drug uptake |
| url | http://link.springer.com/article/10.1186/s13071-020-3972-z |
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