Comparative analysis of the transcriptional responses of five Leishmania species to trivalent antimony

Background: Leishmaniasis is a neglected tropical disease caused by several species of Leishmania. The resistance phenotype of these parasites depends on the characteristics of each species, which contributes to increased therapeutic failures. Understanding the mechanism used by the parasite to survive under treatment pressure in order to identify potential common and specific therapeutic targets is essential for the control of leishmaniasis. The aim of this study was to investigate the expression profiles and potential shared and specific resistance markers of the main Leishmania species of medical importance [subgenus L. (Leishmania): L. donovani, L. infantum and L. amazonensis; subgenus L. (Viannia): L. panamensis and L. braziliensis)] resistant and sensitive to trivalent stibogluconate -(SbIII). Methods: We conducted comparative analysis of the transcriptomic profiles (only coding sequences) of lines with experimentally induced resistance to -SbIII from biological replicates of five Leishmania species available in the databases of four articles based on ortholog attribution. Simultaneously, we carried out functional analysis of ontology and reconstruction of metabolic pathways of the resulting differentially expressed genes (DEGs). Results: Resistant lines for each species had differential responses in metabolic processes, compound binding, and membrane components concerning their sensitive counterpart. One hundred and thirty-nine metabolic pathways were found, with the three main pathways comprising cysteine and methionine metabolism, glycolysis, and the ribosome. Differentially expressed orthologous genes assigned to species-specific responses predominated, with 899 self- genes. No differentially expressed genes were found in common among the five species. Two common upregulated orthologous genes were found among four species (L. donovani, L. braziliensis, L. amazonensis, and L. panamensis) related to an RNA-binding protein and the NAD(P)H cytochrome-B5-oxidoreductase complex, associated with transcriptional control and de novo synthesis of linoleic acid, critical mechanisms in resistance to antimonials. Conclusion: Herein, we identified potential species-specific genes related to resistance to -Sb-III. Therefore, we suggest that future studies consider a treatment scheme that is species-specific. Despite the limitations of our study, this is the first approach toward unraveling the pan-genus genetic mechanisms of resistance in leishmaniasis.

Automated summary

Investigating the expression profiles and potential resistance markers of different Leishmania species revealed species-specific genes related to resistance to trivalent stibogluconate, suggesting the importance of considering a species-specific treatment scheme in controlling leishmaniasis.