Leishmania spp.: proficiency of drug-resistant parasites

Natera, Sonimar; Machuca, Claudia; Padrón-Nieves, Maritza; Romero, Amarilis; Díaz, E; Ponte-Sucre, Alicia

doi:10.1016/j.ijantimicag.2007.01.004

Cited by 98 publications

(60 citation statements)

References 59 publications

(87 reference statements)

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“…In vitro susceptibility testing with live Leishmania stages still remains the primary tool for epidemiological mapping of drug resistance, as molecular resistance markers have not yet been identified or fully validated (17,21,25). Evaluation of the susceptibility of isolates from patient-derived diagnostic material is still hampered by the lack of reliable and reproducible in on April 1, 2019 by guest http://aac.asm.org/ vitro models, and prediction of the treatment outcome is even more controversial (26,32).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Sensitivity Testing of Leishmania Clinical Field Isolates: Preconditioning of Promastigotes Enhances Infectivity for Macrophage Host Cells

Luz

Vermeersch

Dujardin

et al. 2009

Antimicrob Agents Chemother

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Diagnostic material from patients with leishmaniasis is generally available as promastigotes, and proper testing for susceptibility to first-line drugs by the intracellular amastigote assay is frequently hampered by the poor infectivity of the promastigotes for the macrophage host cell. Several conditions for optimization of the in vitro metacyclogenesis and cell infectivity of Leishmania donovani, L. guyanensis, and L. braziliensis field strains obtained from patients receiving standard antimony medication were investigated. Triggering logphase promastigotes to become amastigote-like by increasing the temperature or acidifying the culture medium was not successful. Adequate metacyclogenesis and the highest levels of macrophage infection were obtained after 5-day-old late-log-phase promastigote cultures were preconditioned at 25°C to pH 5.4 for 24 h in Schneider's medium prior to infection. The susceptibility assay with primary peritoneal mouse macrophages included pentavalent antimony (Sb V ; sodium stibogluconate), trivalent antimony (Sb III ; potassium antimonyl tartrate), miltefosine, and the experimental drug PX-6518. All strains were sensitive to miltefosine (50% inhibitory concentration [IC 50 ] < 10 M) and PX-6518 (IC 50 < 2 g/ml) but showed distinct susceptibility to Sb V and/or Sb III , depending on whether they were derived from cured, relapse, or nonresponder patients. Within the available set of Leishmania species and strains, simultaneous Sb V -Sb III resistance was clearly associated with treatment failure; however, a larger set of isolates is still needed to judge the predictive value of Sb V -Sb III susceptibility profiling on treatment outcome. In conclusion, the proposed conditioning protocol further contributes toward a more standardized laboratory model for evaluation of the drug sensitivities of field isolates.As the failure of first-line treatment for all clinical forms of leishmaniasis is a growing problem, it is pivotal to monitor the efficacy of standard drugs and map the prevalence of drug resistance in areas where the disease is endemic (7,9,24). Diagnostic field isolates are mostly provided to the laboratory as promastigotes, but it remains an experimental challenge to appropriately adapt them to the amastigote-macrophage model, still considered the "gold standard" for susceptibility evaluation (23, 31). Infection of the macrophage is generally achieved with metacyclic promastigotes, but unfortunately, infection is subject to a high degree of variability, among several other factors affecting the outcome of the sensitivity test (8, 10). These factors strongly suggest the need for the further standardization of susceptibility testing of clinical field isolates.In the normal course of events, infective metacyclic promastigotes are inoculated by the sand fly into the mammalian host, where they rapidly penetrate susceptible cells, undergo intracellular transformation to the amastigote form, and start dividing. The procyclic and metacyclic phases observed during in vitro culture appear to...

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Section: Discussionmentioning

confidence: 99%

In Vitro Sensitivity Testing of Leishmania Clinical Field Isolates: Preconditioning of Promastigotes Enhances Infectivity for Macrophage Host Cells

Luz

Vermeersch

Dujardin

et al. 2009

Antimicrob Agents Chemother

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“…[5][6][7][8][9] Resistance to antileishmanial drugs has also been observed in Leishmania parasites. 10 Furthermore, as the drugs used in treatment are so expensive, their use is mostly limited in undeveloped and developing countries. Ineffectiveness of drugs against several species of Leishmania is another disadvantage.…”

Section: Introductionmentioning

confidence: 99%

Antileishmanial effect of silver nanoparticles and their enhanced antiparasitic activity under ultraviolet light

Allahverdiyev¹,

Abamor²,

Bağırova³

et al. 2011

IJN

183

116

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Leishmaniasis is a protozoan vector-borne disease and is one of the biggest health problems of the world. Antileishmanial drugs have disadvantages such as toxicity and the recent development of resistance. One of the best-known mechanisms of the antibacterial effects of silver nanoparticles (Ag-NPs) is the production of reactive oxygen species to which Leishmania parasites are very sensitive. So far no information about the effects of Ag-NPs on Leishmania tropica parasites, the causative agent of leishmaniasis, exists in the literature. The aim of this study was to investigate the effects of Ag-NPs on biological parameters of L. tropica such as morphology, metabolic activity, proliferation, infectivity, and survival in host cells, in vitro. Consequently, parasite morphology and infectivity were impaired in comparison with the control. Also, enhanced effects of Ag-NPs were demonstrated on the morphology and infectivity of parasites under ultraviolet (UV) light. Ag-NPs demonstrated significant antileishmanial effects by inhibiting the proliferation and metabolic activity of promastigotes by 1.5- to threefold, respectively, in the dark, and 2- to 6.5-fold, respectively, under UV light. Of note, Ag-NPs inhibited the survival of amastigotes in host cells, and this effect was more significant in the presence of UV light. Thus, for the first time the antileishmanial effects of Ag-NPs on L. tropica parasites were demonstrated along with the enhanced antimicrobial activity of Ag-NPs under UV light. Determination of the antileishmanial effects of Ag-NPs is very important for the further development of new compounds containing nanoparticles in leishmaniasis treatment.

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“…leads to clinical presentations that can range from skin lesions to fatal visceral injuries. Leishmaniasis can be caused by at least 17 different subtypes of parasites and affects .12 million people worldwide in tropical and subtropical areas (1). Leishmania are organisms that have two forms in their life cycle and preferentially infect macrophages in their mammalian hosts.…”

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confidence: 99%

Leukotriene B4 Modulates P2X7 Receptor–Mediated Leishmania amazonensis Elimination in Murine Macrophages

Chaves

Marques-da-Silva

Monteiro

et al. 2014

The Journal of Immunology

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ATP is an important signaling molecule in the immune system, and it is able to bind the P2X7 purinergic receptor. Recently, our group showed that ATP-treated macrophages eliminate Leishmania amazonensis. It has been reported that leukotriene B4 (LTB4) reduces the parasitic load of infected macrophages. Additionally, it has been demonstrated that the P2X7 receptor can induce PLA2 activation and arachidonic acid mobilization. Based on these findings, we investigated whether LTB4 is produced upon P2X7 receptor activation and examined whether LTB4 modulates parasite elimination. Using macrophages lacking the P2X7 receptor, we observed that ATP was not able to reduce L. amazonensis load. This result suggests a role of the P2X7 purinergic receptor in parasite elimination. In addition, ATP was sufficient to induce LTB4 release from infected control macrophages but not from macrophages lacking the P2X7 receptor. Moreover, we found that ATP failed to decrease the parasitic load in 5-lipoxygenase (LO)–deficient macrophages. Treatment with the 5-LO inhibitor AA861 also impairs the ATP effect on parasitic loads. Furthermore, macrophages from 5-LO knockout mice eliminated L. amazonensis in the presence of exogenous LTB4, and macrophages obtained from P2X7 receptor knockout mice eliminated L. amazonensis when incubated with ionomycin. Finally, we demonstrated that in the presence of CP105696, an antagonist for LTB4 high-affinity receptor, ATP was not able to reduce parasitic load. These results indicate that P2X7 receptor activation leads to LTB4 formation, which is required for L. amazonensis elimination.

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Leishmania spp.: proficiency of drug-resistant parasites

Cited by 98 publications

References 59 publications

In Vitro Sensitivity Testing of Leishmania Clinical Field Isolates: Preconditioning of Promastigotes Enhances Infectivity for Macrophage Host Cells

In Vitro Sensitivity Testing of Leishmania Clinical Field Isolates: Preconditioning of Promastigotes Enhances Infectivity for Macrophage Host Cells

Antileishmanial effect of silver nanoparticles and their enhanced antiparasitic activity under ultraviolet light

Leukotriene B4 Modulates P2X7 Receptor–Mediated Leishmania amazonensis Elimination in Murine Macrophages

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