Upregulation of antioxidant genes in antimony-resistant Leishmania tropica clinical isolates.

BACKGROUND

Increasing resistance to antimonial drugs has become a significant challenge in effective treatment in endemic regions of leishmaniasis. Antioxidant defense plays a crucial role in antimony resistance by combating antimonial-induced oxidative stress. Accordingly, we investigated the transcript levels of some antioxidant genes in antimony-sensitive and resistant clinical Leishmania tropica isolates.

METHODS

In the current study, 22 Leishmania tropica isolates from ACL patients who presented responsive or unresponsive to antimony were examined. The susceptibility of parasites against SbV and hydrogen peroxide (H2O2) was analyzed. We evaluated the transcript levels of five genes, including cytosolic and mitochondrial tryparedoxin (cTXN, mTXN), cytosolic and mitochondrial tryparedoxin peroxidase (cTXNPx, mTXNPx), and ascorbate peroxidase (APX) in antimony-sensitive and resistant L. tropica clinical isolates.

RESULTS

The in-vitro susceptibility to SbV in intracellular amastigotes revealed 3.82 times higher IC50 in resistant isolates compared to sensitive ones. The IC50 toward H2O2 in resistant isolates was 1.6 times higher than in sensitive ones, positively correlated with SbV IC50 values. The average transcript expression level of cTXNPx, mTXNPx, cTXN, and APX genes significantly increased in resistant isolates by 2.51, 1.69, 2.41, and 2.12-fold compared to sensitive ones. The highest correlation coefficient between the gene expression and SbV IC50 values belonged to the cTXNPx, cTXN, APX, mTXN, and mTXNPx genes, respectively. The average transcript expression level of cytosolic TXN and TXNPx in resistant L. tropica isolates was higher than its mitochondrial counterpart.

CONCLUSIONS

The data presented here revealed a phenotypic heterogeneity in antioxidant gene expression among L. tropica clinical isolates. Overall, the upregulation of genes involved in antioxidant defense could probably contribute to natural antimony resistance in L. tropica clinical isolates.