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Profiling gene expression of antimony response genes in Leishmania (Viannia) panamensis and infected macrophages and its relationship with drug susceptibility.
Acta Trop. 2017 Dec; 176:355-363.AT

Abstract

The mechanisms of Leishmania resistance to antimonials have been primarily determined in experimentally derived Leishmania strains. However, their participation in the susceptibility phenotype in field isolates has not been conclusively established. Being an intracellular parasite, the activity of antileishmanials is dependent on internalization of drugs into host cells and effective delivery to the intracellular compartments inhabited by the parasite. In this study we quantified and comparatively analyzed the gene expression of nine molecules involved in mechanisms of xenobiotic detoxification and Leishmania resistance to antimonial drugs in resistant and susceptible laboratory derived and clinical L.(Viannia) panamensis strains(n=19). In addition, we explored the impact of Leishmania susceptibility to antimonials on the expression of macrophage gene products having putative functions in transport, accumulation and metabolism of antimonials. As previously shown for other Leishmania species, a trend of increased abcc3 and lower aqp-1 expression was observed in the laboratory derived Sb-resistant L.(V.) panamensis line. However, this was not found in clinical strains, in which the expression of abca2 was significantly higher in resistant strains as both, promastigotes and intracellular amastigotes. The effect of drug susceptibility on host cell gene expression was evaluated on primary human macrophages from patients with cutaneous leishmaniasis (n=17) infected ex-vivo with the matched L.(V.) panamensis strains isolated at diagnosis, and in THP-1 cells infected with clinical strains (n=6) and laboratory adapted L.(V.) panamensis lines. Four molecules, abcb1 (p-gp), abcb6, aqp-9 and mt2a were differentially modulated by drug resistant and susceptible parasites, and among these, a consistent and significantly increased expression of the xenobiotic scavenging molecule mt2a was observed in macrophages infected with Sb-susceptible L. (V.) panamensis. Our results substantiate that different mechanisms of drug resistance operate in laboratory adapted and clinical Leishmania strains, and provide evidence that parasite-mediated modulation of host cell gene expression of molecules involved in drug transport and metabolism could contribute to the mechanisms of drug resistance and susceptibility in Leishmania.

Authors+Show Affiliations

Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Carrera 125 No. 19-225 Cali, Colombia.Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Carrera 125 No. 19-225 Cali, Colombia.Yale School of Medicine and Yale School of Public Health, New Haven, CT, USA.Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Carrera 125 No. 19-225 Cali, Colombia.Yale School of Public Health, New Haven, CT, USA.Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Carrera 125 No. 19-225 Cali, Colombia.Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Carrera 125 No. 19-225 Cali, Colombia. Electronic address: mgomez@cideim.org.co.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28843396

Citation

Barrera, Maria Claudia, et al. "Profiling Gene Expression of Antimony Response Genes in Leishmania (Viannia) Panamensis and Infected Macrophages and Its Relationship With Drug Susceptibility." Acta Tropica, vol. 176, 2017, pp. 355-363.
Barrera MC, Rojas LJ, Weiss A, et al. Profiling gene expression of antimony response genes in Leishmania (Viannia) panamensis and infected macrophages and its relationship with drug susceptibility. Acta Trop. 2017;176:355-363.
Barrera, M. C., Rojas, L. J., Weiss, A., Fernandez, O., McMahon-Pratt, D., Saravia, N. G., & Gomez, M. A. (2017). Profiling gene expression of antimony response genes in Leishmania (Viannia) panamensis and infected macrophages and its relationship with drug susceptibility. Acta Tropica, 176, 355-363. https://doi.org/10.1016/j.actatropica.2017.08.017
Barrera MC, et al. Profiling Gene Expression of Antimony Response Genes in Leishmania (Viannia) Panamensis and Infected Macrophages and Its Relationship With Drug Susceptibility. Acta Trop. 2017;176:355-363. PubMed PMID: 28843396.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Profiling gene expression of antimony response genes in Leishmania (Viannia) panamensis and infected macrophages and its relationship with drug susceptibility. AU - Barrera,Maria Claudia, AU - Rojas,Laura Jimena, AU - Weiss,Austin, AU - Fernandez,Olga, AU - McMahon-Pratt,Diane, AU - Saravia,Nancy G, AU - Gomez,Maria Adelaida, Y1 - 2017/08/24/ PY - 2017/04/14/received PY - 2017/08/04/revised PY - 2017/08/17/accepted PY - 2017/8/28/pubmed PY - 2018/4/3/medline PY - 2017/8/28/entrez KW - ABC transporter KW - Aquaporin KW - Leishmania Viannia panamensis KW - Macrophage KW - Meglumine antimoniate SP - 355 EP - 363 JF - Acta tropica JO - Acta Trop VL - 176 N2 - The mechanisms of Leishmania resistance to antimonials have been primarily determined in experimentally derived Leishmania strains. However, their participation in the susceptibility phenotype in field isolates has not been conclusively established. Being an intracellular parasite, the activity of antileishmanials is dependent on internalization of drugs into host cells and effective delivery to the intracellular compartments inhabited by the parasite. In this study we quantified and comparatively analyzed the gene expression of nine molecules involved in mechanisms of xenobiotic detoxification and Leishmania resistance to antimonial drugs in resistant and susceptible laboratory derived and clinical L.(Viannia) panamensis strains(n=19). In addition, we explored the impact of Leishmania susceptibility to antimonials on the expression of macrophage gene products having putative functions in transport, accumulation and metabolism of antimonials. As previously shown for other Leishmania species, a trend of increased abcc3 and lower aqp-1 expression was observed in the laboratory derived Sb-resistant L.(V.) panamensis line. However, this was not found in clinical strains, in which the expression of abca2 was significantly higher in resistant strains as both, promastigotes and intracellular amastigotes. The effect of drug susceptibility on host cell gene expression was evaluated on primary human macrophages from patients with cutaneous leishmaniasis (n=17) infected ex-vivo with the matched L.(V.) panamensis strains isolated at diagnosis, and in THP-1 cells infected with clinical strains (n=6) and laboratory adapted L.(V.) panamensis lines. Four molecules, abcb1 (p-gp), abcb6, aqp-9 and mt2a were differentially modulated by drug resistant and susceptible parasites, and among these, a consistent and significantly increased expression of the xenobiotic scavenging molecule mt2a was observed in macrophages infected with Sb-susceptible L. (V.) panamensis. Our results substantiate that different mechanisms of drug resistance operate in laboratory adapted and clinical Leishmania strains, and provide evidence that parasite-mediated modulation of host cell gene expression of molecules involved in drug transport and metabolism could contribute to the mechanisms of drug resistance and susceptibility in Leishmania. SN - 1873-6254 UR - https://www.unboundmedicine.com/medline/citation/28843396/Profiling_gene_expression_of_antimony_response_genes_in_Leishmania__Viannia__panamensis_and_infected_macrophages_and_its_relationship_with_drug_susceptibility_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0001-706X(17)30435-7 DB - PRIME DP - Unbound Medicine ER -