Antimony resistance in Leishmania (Viannia) braziliensis clinical isolates from atypical lesions associates with increased ARM56/ARM58 transcripts and reduced drug uptake

Rugani, Jerônimo Nunes; Gontijo, Célia Maria Ferreira; Frézard, Frédéric; Soares, Rodrigo Pedro; Monte-Neto, Rubens L.

doi:10.1590/0074-02760190111

Cited by 18 publications

(16 citation statements)

References 27 publications

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“…clinical isolates. can increase this complexity 52 – 54 . This panorama is aggravated by therapeutic regimens with the first-line drug that varies from a high (20 mg/kg/day) to a low dose (5 mg/kg/day) in Brazil’ endemic areas, since response to treatment with antimonial drugs varies depending on the parasite strain involved 55 .…”

Section: Discussionmentioning

confidence: 99%

“…However, promastigotes and axenic amastigotes of all NR isolates showed increased subtilisin (LbrM.13.0860) or TXNPx (LbrM.15.1080) expression. Since antimony resistance can be related to other processes, such as drug uptake and efflux, it is recommended to evaluate a broad set of molecular markers in resistance predictive assays using clinical isolates 54 . Thus, our results suggest that subtilisin (LbrM.13.0860) could be an additional marker during molecular characterizations of L. ( V. ) braziliensis .…”

Section: Discussionmentioning

confidence: 99%

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Serine proteases profiles of Leishmania (Viannia) braziliensis clinical isolates with distinct susceptibilities to antimony

Zabala-Peñafiel

Dias-Lopes

Cysne-Finkelstein

et al. 2021

Sci Rep

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Glucantime (SbV) is the first-line treatment against American Tegumentary Leishmaniasis. Resistance cases to this drug have been reported and related to host characteristics and parasite phenotypes. In this study, 12 Leishmania (Viannia) braziliensis isolates from patients that presented clinical cure (Responders—R) and relapse or therapeutic failure (Non-responders—NR) after treatment with antimony, were analyzed. These parasites were assessed by in vitro susceptibility to SbIII and SbV, serine proteases activity measured with substrate (z-FR-AMC) and specific inhibitors (TLCK, AEBSF and PMSF). In vitro susceptibility of axenic amastigotes to SbIII showed a significant difference between R and NR groups. The protease assays showed that TLCK inhibited almost 100% of activity in both axenic amastigotes and promastigotes while AEBSF inhibited around 70%, and PMSF showed lower inhibition of some isolates. Principal component and clustering analysis performed with these data yielded one homogeneous cluster with only NR isolates and three heterogeneous clusters with R and NR isolates. Additionally, differential expression of subtilisins (LbrM.13.0860 and LbrM.28.2570) and TXNPx (LbrM.15.1080) was evaluated in promastigotes and axenic amastigotes from both groups. The results showed a higher expression of LbrM.13.0860 and LbrM.15.1080 genes in axenic amastigotes, while LbrM.28.2570 gene had the lowest expression in all isolates, regardless of the parasite form. The data presented here show a phenotypic heterogeneity among the parasites, suggesting that exploration of in vitro phenotypes based on SbIII and serine proteases profiles can aid in the characterization of L. (V.) braziliensis clinical isolates.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Serine proteases profiles of Leishmania (Viannia) braziliensis clinical isolates with distinct susceptibilities to antimony

Zabala-Peñafiel

Dias-Lopes

Cysne-Finkelstein

et al. 2021

Sci Rep

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“…Leishmania spp. resistance towards antimony treatment is an increasing multifactorial phenomenon, and several virulence factors have been studied and related to resistant phenotypes in clinical isolates [39,[61][62][63]. The present study aids to this discussion by bringing proteases to focus, one of the most studied parasite virulence factors in the last 30 years [18,22,64].…”

Section: Discussionmentioning

confidence: 82%

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

Zabala-Peñafiel¹,

Dias-Lopes²,

Cysne-Finkelstein

et al. 2021

Preprint

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Glucantime® (SbV) is the first-line treatment against leishmaniasis in South America. Its effectiveness has been associated with modulation of the parasite detoxification system that, in turn, is related to serine proteases such as subtilisins. In this study, 12 Leishmania (Viannia) braziliensis isolates from patients that presented clinical cure (Responders - R) and relapse or therapeutic failure (Non-responders - NR) were used. The parasites were assessed by in vitro susceptibility to SbIII and SbV, serine proteases activity – measured with z-FR-AMC as substrate and specific inhibitors – and expression of subtilisins and tryparedoxin-peroxidase (TXNPx). In vitro susceptibility of axenic amastigotes to SbIII showed a significant difference between R and NR groups. TLCK inhibited almost 100 % of activity in both axenic amastigotes and promastigotes while AEBSF inhibited around 70 %, and PMSF showed lower inhibition of specific isolates. Principal component and clustering analysis yielded one homogeneous cluster with only NR isolates and three heterogeneous clusters with R and NR isolates. Additionally, transcripts of subtilisins (LbrM.13.0860 and LbrM.28.2570) and TXNPx (LbrM.15.1080) were detected in promastigotes and axenic amastigotes from both groups. The data presented here show a phenotypic heterogeneity among the parasites, suggesting that exploration of in vitro phenotypes based on SbIII and serine proteases profiles can aid in the characterization of L. (V.) braziliensis clinical isolates.

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“…(45) On the other hand, L. braziliensis isolates with reduced drug uptake have been recovered from atypical lesions, and some mutant variants of L. guyanensis strains are resistant to pentavalent antimonials, the first-line treatment option for CL in Panama. (46,47) Interestingly, a poor response to antimonial or pentamidine therapy has already been described in patients infected with L. naiffi. (48) Thus, the sympatric circulation of different Leishmania species from subgenus Viannia in Panama should be further studied because it might have significance regarding human disease pathogenesis and control.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of cytochrome b sequence to identify Leishmania species and variants: the case of Panama

Davila

Pineda

Calzada

et al. 2021

Mem. Inst. Oswaldo Cruz

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BACKGROUND The genetic heterogeneity of Leishmania parasites is a major factor responsible for the wide variety of Leishmania-associated manifestations. Consequently, understanding the genetic make-up of Leishmania species using suitable molecular markers is an important component of realising local and regional scale disease risk. The cytochrome b (cytb) is frequently used to type New World Leishmania species. However, its potential to discriminate Leishmania species and variants requires further evaluation.OBJECTIVES To explore the capacity of cytb gene to identify New World Leishmania species and variants and to develop an approach able to type local Leishmania species and variants.METHODS We retrieved 360 partial and complete Leishmania cytb gene sequences publicly available in GenBank database to study all single nucleotide polymorphisms (SNPs) across the cytb gene that differentiate New World Leishmania species. This information was used to develop an approach based upon the polymorphisms found in a DNA segment of 948bp. We also compared the typing results found with this technique with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) profiling obtained using HSP70 gene as target. One hundred Panamanian isolates were used to both typed Leishmania species and assess local genetic variability.FINDINGS We found complete agreement between our cytb approach and the PCR-RFLP profiling method based on HSP70 for Leishmania species identification. Ninety-two isolates were identified as L. panamensis, although other Viannia species were found circulating at a lower frequency. Three L. panamensis haplotypes were identified in Panamanian provinces. We also provide an initial report of L. guyanensis haplotypes circulating in Panama.MAIN CONCLUSIONS Cytb gene sequence encompasses key main SNPs that aid to identify Leishmania species. The cytb approach developed with this information was able to identify and assess genetic variability of local Leishmania species found in this study. Key words: leishmaniasis -cytochrome b gene -haplotypes -Leishmania panamensis -Leishmania guyanensis -PanamaLeishmaniasis, a neglected tropical disease transmitted by female sandflies and caused by kinetoplastic protozoa parasites of the genus Leishmania, is endemic in 98 countries worldwide. Due to the high number of cases and its geographical expansion, the World Health Organization (WHO) considers leishmaniasis as an emerging/ reemerging vector borne parasitic disease. (1) Regarding its impact on public health, leishmaniasis has an estimated annual incidence of 2.0 million cases and an approximated prevalence of 12,000,000 cases. (2) In addition, this disease is responsible for 20,000 to 40,000 deaths occurring in rural and suburban populations all year round. (1,2) Visceral and tegumentary leishmaniasis are the main clinical forms of the disease which show different clinical expressions depending upon the species of Leishmania responsible for the disease, the genetic background and immunological status of ...

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Antimony resistance in Leishmania (Viannia) braziliensis clinical isolates from atypical lesions associates with increased ARM56/ARM58 transcripts and reduced drug uptake

Cited by 18 publications

References 27 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

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

Evaluation of cytochrome b sequence to identify Leishmania species and variants: the case of Panama

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