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Insights Into the Trypanothione System in Antimony-Resistant and Sensitive Leishmania Tropica Clinical Isolates Publisher Pubmed



Valashani HT1, 2 ; Ahmadpour M1, 2 ; Naddaf SR1 ; Mohebali M3 ; Hajjaran H3 ; Latifi A3, 4 ; Salimi M5 ; Farahmand M1 ; Naeimi S1 ; Raissi V3 ; Kazemirad E3
Authors
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Authors Affiliations
  1. 1. Department of Parasitology, Pasteur Institute of Iran, Tehran, Iran
  2. 2. Department of Biology, Central Tehran Branch, Islamic Azad University, Tehran, Iran
  3. 3. Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Department of Clinical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran

Source: Acta Tropica Published:2024


Abstract

Pentavalent antimonials are the mainstay treatment against different clinical forms of leishmaniasis. The emergence of resistant isolates in endemic areas has led to treatment failure. Unraveling the underlying resistance mechanism would assist in improving the treatment strategies against resistant isolates. This study aimed to investigate the RNA expression level of glutathione synthetase (GS), Spermidine synthetase (SpS), trypanothione synthetase (TryS) genes involved in trypanothione synthesis, and thiol-dependent reductase (TDR) implicated in drug reduction, in antimony-sensitive and -resistant Leishmania tropica isolates. We investigated 11 antimony-resistant and 11 antimony-sensitive L. tropica clinical isolates from ACL patients. Drug sensitivity of amastigotes was determined in mouse macrophage cell line J774A.1. The RNA expression level in the promastigote forms was analyzed by quantitative real-time PCR. The results revealed a significant increase in the average expression of GS, SpS, and TrpS genes by 2.19, 1.56, and 2.33-fold in resistant isolates compared to sensitive ones. The average expression of TDR was 1.24-fold higher in resistant isolates, which was insignificant. The highest correlation coefficient between inhibitory concentration (IC50) values and gene expression belonged to the TryS, GS, SpS, and TDR genes. Moreover, the intracellular thiol content was increased 2.17-fold in resistant isolates compared to sensitive ones and positively correlated with IC50 values. Our findings suggest that overexpression of trypanothione biosynthesis genes and increased thiol content might play a key role in the antimony resistance of L. tropica clinical isolates. In addition, the diversity of gene expression in the trypanothione system and thiol content among L. tropica clinical isolates highlighted the phenotypic heterogeneity of antimony resistance among the parasite population. © 2024
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