New Insights on Drug-Resistant Clinical Isolates of Leishmania infantum-Infected Human Macrophages as Determined by Comparative Transcriptome Analyses

Leishmaniasis is the second most important neglected tropical parasitic disease after malaria. This disease is distributed worldwide and can be present in a variety of clinical forms, depending on the parasite species and host's genetic background. As chemotherapy is the only effective weapon whose effectiveness is limited by the frequent appearance of drug resistance and therapeutic failure, new therapeutic strategies are required. To better understand the factors that contribute to therapeutic failure and drug resistance in leishmaniasis, we studied the transcriptomic changes in host THP-1 cells after infection with clinical Leishmania infantum isolates with different susceptibilities to antileishmanial drugs by RNA-seq. Analysis of the differentially expressed genes (DEGs) in infected host cells revealed variations in DEG numbers in the THP-1-infected cells depending on the Leishmania line. A key conclusion of this study is that the modulation of host cells is Leishmania line dependent.Gene ontology enrichment analyses of DEGs indicated that certain biological processes were modulated in the infected host cells, specifically related to cellular metabolism, immune response, defense response, signaling pathways, and cell proliferation and apoptosis. Furthermore, this study provides new potential therapeutic markers and insights into the THP-1 host transcriptomic changes that occur after late infection with drug-resistant L. infantum clinical isolates.