Miltefosine enhances the fitness of a non-virulent drug-resistant<i>Leishmania infantum</i>strain

Eberhardt, E.; Bulté, Dimitri; Bockstal, Lieselotte Van; Kerkhof, Magali Van den; Cos, Paul; Delputte, Peter; Hendrickx, Sarah; Maes, Louis; Caljon, Guy

doi:10.1093/jac/dky450

Cited by 22 publications

(53 citation statements)

References 44 publications

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“…Post-treatment relapse in the field has been linked to only a minor decrease in MIL susceptibility, with this 'intermediate' resistant phenotype behaving similarly to the non-exposed wild-type strains [35]. This contrasts with other studies describing an increased infectivity for relapse-derived strains [3,5] which is actually unexpected given the detrimental changes in fitness upon aqcuisition of full resistance [13,14,29].…”

Section: Discussionmentioning

confidence: 81%

“…For example, involvement of host-related parameters linking treatment failure and post-treatment relapse to drug pharmacokinetics and dynamics (PK/PD) have already been indicated [26,27] as well as the link of MIL relapse to both drug-related and parasite-related factors [28]. It was shown that a MIL-resistant phenotype can impact on parasite fitness [13,14,29] and that clinical MIL relapse may be associated with enhanced infectivity [3]. The present laboratory study specifically aimed to evaluate the phenotypic impact of repeated MIL exposure using syngeneic strains obtained through both in vitro and in vivo selection procedures [15,16].…”

Section: Discussionmentioning

confidence: 99%

“…No significant differences could be observed between WT-and MIL-exposed strains. The represented data are combined from 2 independent experiments with a minimum of 10 flies for each group and time point amastigotes both in vitro and in vivo failed to result in a drug-resistant phenotype [15,34], creating the possibility to assess the impact of repeated MIL exposure without the alterations in parasite fitness as observed with full MIL resistance [13,14,29]. In the present study, recurrent in vitro and in vivo MIL exposure only resulted in a marginal decrease in promastigote susceptibility, which corroborates other studies describing the existence of an 'intermediate' resistant phenotype characterized by a partial decrease in susceptibility as a step towards full resistance [31].…”

Section: Discussionmentioning

confidence: 99%

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Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection

et al. 2020

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“…Ex vivo amastigotes of L. infantum ITMAP263 were obtained from the spleen of heavily infected donor hamsters and purified using two centrifugation steps as described elsewhere (28). The strains for the in vivo infections were the bioluminescent L. infantum MHOM/FR/96/LEM3323 PpyRE9 and MHOM/MA/67/ITMAP263 PpyRE9 , generated by the stable introduction of the red-shifted firefly luciferase PpyRE9 using the pLEXSY-hyg2.1 vector (29 Figure 1A).…”

Section: Parasite Species/strainsmentioning

confidence: 99%

“…Upon induction, mice were imaged in the IVIS R chamber for 10 min. Images were analyzed using LivingImage v4.3.1 within regions of interest (ROI) corresponding with the liver (29).…”

Section: In Vivo Infections With Vl Strainsmentioning

confidence: 99%

Interferon Alpha Favors Macrophage Infection by Visceral Leishmania Species Through Upregulation of Sialoadhesin Expression

et al. 2020

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Type I interferons (IFNs) induced by an endogenous Leishmania RNA virus or exogenous viral infections have been shown to exacerbate infections with New World Cutaneous Leishmania parasites, however, the impact of type I IFNs in visceral Leishmania infections and implicated mechanisms remain to be unraveled. This study assessed the impact of type I IFN on macrophage infection with L. infantum and L. donovani and the implication of sialoadhesin (Siglec-1/CD169, Sn) as an IFN-inducible surface receptor. Stimulation of bone marrow-derived macrophages with type I IFN (IFN-α) significantly enhanced susceptibility to infection of reference laboratory strains and a set of recent clinical isolates. IFN-α particularly enhanced promastigote uptake. Enhanced macrophage susceptibility was linked to upregulated Sn surface expression as a major contributing factor to the infection exacerbating effect of IFN-α. Stimulation experiments in Sn-deficient macrophages, macrophage pretreatment with a monoclonal anti-Sn antibody or a novel bivalent anti-Sn nanobody and blocking of parasites with soluble Sn restored normal susceptibility levels. Infection of Sn-deficient mice with bioluminescent L. infantum promastigotes revealed a moderate, strain-dependent role for Sn during visceral infection under the used experimental conditions. These data indicate that IFN-responsive Sn expression can enhance the susceptibility of macrophages to infection with visceral Leishmania promastigotes and that targeting of Sn may have some protective effects in early infection.

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Target-Based Rational Improvement Strategies and Pitfalls in Leishmania Drug Discovery

Gupta,

Goicoechea,

Vance

et al. 2023

Natural Product Based Drug Discovery Against Human Parasites

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Miltefosine enhances the fitness of a non-virulent drug-resistantLeishmania infantumstrain

Cited by 22 publications

References 44 publications

Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection

Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection

Interferon Alpha Favors Macrophage Infection by Visceral Leishmania Species Through Upregulation of Sialoadhesin Expression

Target-Based Rational Improvement Strategies and Pitfalls in Leishmania Drug Discovery

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