Abstract
Macrophages are the principal host cells of Leishmania spp. in human infection and play a critical role in controlling infection and enabling parasite survival and persistence. Nevertheless, understanding of drug resistance in leishmaniasis has primarily focused on the parasite. This investigation provides evidence of the significant differential macrophage response to ex vivo infection with clinical strains of L. (V.) panamensis naturally resistant (zymodeme 2.3/zym 2.3) or sensitive (zymodeme 2.2/zym 2.2) to antimonial drug, and the distinct effect of this drug on the activation of macrophages. Transcriptome analysis of infected monocyte-derived macrophages from healthy donors revealed significant interferon and cytokine signaling in response to zym 2.3 strains compared to zym 2.2 strains. Furthermore, in the presence of antimony, macrophages infected with zym 2.3 strains, but not with zym 2.2 strains, significantly increased the expression of genes associated with M-CSF-generated macrophages (M-MØ, anti-inflammatory). Notably, macrophages infected with zym 2.3 strains exhibited elevated expression of genes associated with control of inflammatory and microbicidal response, such as the IDO1/IL4I1-Kyn-AHR pathways and superoxide dismutase, and downregulation of transporters like ABC and AQP, compared to macrophages infected with zym 2.2 strains. Remarkably, the majority of these pathways remained upregulated even in the presence of the strong modulatory effect of antimonial drug. Together, these findings demonstrate that the initial and specific parasite-host interaction influences the ex vivo macrophage response to antimony. Identification of key pathways in macrophage responses associated with natural resistance to this antileishmanial, enhances understanding of host-response mechanisms in the outcome of Leishmania infection and response to treatment.