Evidence of Subpopulations with Distinct Biological Features Within a Leishmania (Viannia) braziliensis Strain

Cysne-Finkelstein, Léa; Silva-Almeida, Mariana; Pereira, Bernardo Acácio Santini; Charret, Karen dos Santos; Bertho, Álvaro Luiz; Bastos, Leonardo Soares; Pinto, Luzia de Oliveira; Oliveira, Francisco Odencio Rodrigues de; Pereira, Mirian Cláudia da Souza; Alves, Carlos Roberto

doi:10.1016/j.protis.2017.11.004

Cited by 14 publications

(18 citation statements)

References 48 publications

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“…This may suggest that, independently of each isolate clinical response, they have common enzymatic and in vitro Sb III susceptibility traits. This observation supports the hypothesis that parasites of the subgenus Viannia are a polyclonal population with high genetic variability and, consequently, phenotypic diversity [20,57]. Other studies have shown that genetic and phenotypic characteristics among different L. (V.) braziliensis strains are associated with different clinical manifestations and drug resistance [46,58].…”

Section: Discussionsupporting

confidence: 85%

“…Each parasite isolate did not have more than 5 passages since isolation. Differentiation from promastigotes to axenic amastigotes was performed as previously described by Cysne-Finkelstein et al [20], with some modi cations. Brie y, 5x10 5 per mL of log-phase promastigotes were cultured in Schneider medium (pH 5.5) supplemented with 20% of FBS, 60 IU penicillin, 60 mg/mL streptomycin and maintained at 26 °C for 2 days.…”

Section: Parasites Culture and In Vitro Differentiationmentioning

confidence: 99%

“…Speci cally, serine proteases have been extensively studied in American Leishmania spp. due to their functional interrelationship in parasite physiology and their potential as therapeutic targets [18][19][20][21][22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

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Serine Proteases Profiles of Leishmania (Viannia) Braziliensis Clinical Isolates With Distinct Susceptibilities to Antimony

Zabala-Peñafiel¹,

Dias-Lopes²,

Cysne-Finkelstein

et al. 2020

Preprint

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Background: Glucantime® (SbV) is considered the first-line treatment against American Tegumentary Leishmaniasis in South America, though increased parasite resistance towards it have been reported and hampered its effectiveness. In this context, subtilisins serine proteases have been related to parasites’ susceptibility to drugs such as SbV and derivatives, through modulation of the parasite detoxification system. However, little is known about parasites causing ATL and their distinct responses towards this treatment.Methods: The study was conducted using Leishmania (Viannia) braziliensis clinical isolates from patients that presented clinical cure or Responders (R) and relapse/therapeutic failure or Non-responders (NR). Twelve clinical isolates were used to assess their in vitro susceptibility to SbIII and SbV, serine proteases activity, and expression of subtilisins-like and tryparedoxin-peroxidase (TXNPx) transcripts. Results: SbIII was able to better distinguish axenic amastigotes from each clinical group. These isolates were also assessed for serine protease activity, using z-FR-AMC as substrate and detecting distinct enzyme profiles with specific inhibitors. TLCK inhibited almost 100% of activity in both promastigotes and axenic amastigotes while AEBSF inhibited around 70%. PMSF showed low inhibition of specific isolates (35%). Gathering all the quantitative data, we performed principal component analysis and then used the K-means algorithm to cluster the isolates. This analysis yielded one cluster with only one isolate (R isolate), one homogeneous cluster (NR isolates), and three heterogeneous clusters (R and NR isolates). Additionally, gene transcripts of subtilisins and TXNPx were detected in promastigotes and axenic amastigotes from both groups. Conclusions: Cluster analysis showed that there is a phenotypic heterogeneity among the isolates, however, exploration of in vitro phenotypes based on SbIII and serine proteases profiles can aid in the characterization and better understanding of L. (V.) braziliensis clinical isolates.

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Section: Discussionsupporting

confidence: 85%

Section: Parasites Culture and In Vitro Differentiationmentioning

confidence: 99%

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Serine Proteases Profiles of Leishmania (Viannia) Braziliensis Clinical Isolates With Distinct Susceptibilities to Antimony

Zabala-Peñafiel¹,

Dias-Lopes²,

Cysne-Finkelstein

et al. 2020

Preprint

Self Cite

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“…Although the extensive literature has revealed intra-and interspecific genetic variability of some Leishmania species (mainly L. donovani, L. major, L. tropica) [23,30,41,42], little is known about the genetic variability of Leishmania (Viannia) species. The reported studies so far have focused on L. braziliensis, where the majority report consistent findings in describing its high intraspecific genetic diversity [16,26,43] even in cell populations isolated from a single L. braziliensis strain ("sub-strain") [44], while in L. panamensis the results are not yet concordant, probably for the molecular approaches used. While studies using MLST reveal extreme genetic homogeneity within L. panamensis [10], others using MLEE [5], sequencing of specific genes (Cytb/HSP70) [6], AFLP [13], or microsatellites [14], have reported a high intraspecific genetic diversity in this species.…”

Section: Discussionmentioning

confidence: 89%

Intraspecific Genomic Divergence and Minor Structural Variations in Leishmania (Viannia) panamensis

Patiño

Muñoz

Muskus

et al. 2020

Genes

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Leishmania (Viannia) panamensis is one of the most important Leishmania species associated with cutaneous leishmaniasis (CL) in Latin America. Despite its wide geographic distribution and pathogenic potential in humans and animals, the genomic variability of this species is low compared with other Leishmania species circulating in the same geographical area. No studies have reported a detailed analysis of the whole genome of L. panamensis from clinical isolates using DNA high-throughput sequencing to clarify its intraspecific genomic variability or plausible divergence. Therefore, this study aimed to evaluate the intraspecific genomic variability of L. panamensis from Colombia and Panama. A total of 22 genomes were analyzed, 19 from Colombian patients with CL and three genomes from Panama obtained from public databases. The phylogenomic analysis revealed the potential existence of three well-supported clades as evidence of intraspecific divergence. Additionally, the whole-genome analysis showed low structural variations in terms of ploidy, copy number variations, and single-nucleotide polymorphisms (SNPs). SNPs shared among all clades were identified, revealing their importance in different biological processes of L. panamensis. The findings not only expand our knowledge of intraspecific genomic variability of one of the most important Leishmania species in South America but also highlights the possible existence of different clades/lineages/subpopulations across a geographic scale.

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“…Peritoneal macrophages were harvested from BALB/c mice as previously described [ 22 ]. Cells were recovered after centrifugation (2 ×, 1800 × g , 10 min, 4 °C) in RPMI 1640 medium containing 10% FCS.…”

Section: Methodsmentioning

confidence: 99%

Antileishmanial Activity of 2-Methoxy-4H-spiro-[naphthalene-1,2′-oxiran]-4-one (Epoxymethoxy-lawsone): A Promising New Drug Candidate for Leishmaniasis Treatment

et al. 2018

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Epoxymethoxy-lawsone is a naphthoquinone derivative promising as drug candidate for the treatment of leishmaniases. In the present work the effectiveness of epoxymethoxylawsone, and meglumine antimoniate on Leishmania (Leishmania) amazonensis parasites and on mice paw lesions of infected BALB/c mice was assessed. In an intracellular amastigotes assay, the half-maximal inhibitory concentration (IC50) value for epoxymethoxylawsone was slightly higher (1.7-fold) than that found for meglumine antimoniate. The efficacy of both drugs became more evident after 48 h of exposure when either the oxirane compound and reference drug reached 18-fold and 7.4-fold lower IC50 values (0.40 ± 0.001 µM and 0.60 ± 0.02 µM), respectively. Promastigotes were also affected by epoxymethoxylawsone after 24 h of incubation (IC50 = 45.45 ± 5.0 µM), but with IC50 6-fold higher than those found for intracellular amastigotes. Cytotoxicity analysis revealed that epoxymethoxylawsone (CC50 = 40.05 ± µM) has 1.7-fold higher effects than meglumine antimoniate (CC50 = 24.14 ± 2.6 µM). Treatment of the paw lesion in infected BALB/c mice with epoxymethoxy-lawsone led to a significant 27% reduction (p < 0.05) of the lesion size, for all administrated doses, compared to the control group. Lesion reduction was also detected after mice treatment with meglumine antimoniate, reaching 31.0% (0.23 mg of Sb(V)/Kg/day and 2.27 mg of Sb(V)/Kg/day) and 64.0% (22.7 mg of Sb(V)/Kg/day). In addition, mice lesion ultrastructural changes were evidenced in amastigotes. The set of data gathered here indicate that epoxymethoxylawsone has pronounced effects on parasites and merits furthering to the preclinical stage.

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Evidence of Subpopulations with Distinct Biological Features Within a Leishmania (Viannia) braziliensis Strain

Cited by 14 publications

References 48 publications

Serine Proteases Profiles of Leishmania (Viannia) Braziliensis Clinical Isolates With Distinct Susceptibilities to Antimony

Serine Proteases Profiles of Leishmania (Viannia) Braziliensis Clinical Isolates With Distinct Susceptibilities to Antimony

Intraspecific Genomic Divergence and Minor Structural Variations in Leishmania (Viannia) panamensis

Antileishmanial Activity of 2-Methoxy-4H-spiro-[naphthalene-1,2′-oxiran]-4-one (Epoxymethoxy-lawsone): A Promising New Drug Candidate for Leishmaniasis Treatment

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