Drug resistance and treatment failure are increasingly recognized in human leishmaniasis. Investigation of resistance has predominantly focused on parasite-mediated mechanisms. This study examines the role of host macrophages in natural resistance to antimonial drug. Our findings reveal distinct responses by macrophages infected with Leishmania (Viannia) panamensis strains that are naturally resistant to antimonial drug versus sensitive strains, both in the presence and absence of the drug. Distinctively, resistant parasites induced regulatory pathways that modulate inflammatory responses and alter host cell transporter expression, potentially contributing to parasite survival under antimony exposure. The host cell-parasite interaction in the context of drug resistant intracellular infections presents opportunities for innovative therapeutic strategies targeting host cell responses. Clinical strains of L. (V . ) panamensis naturally resistant or sensitive to antimonial drug (SbV) induce different profiles of human macrophage activation. L. (V . ) panamensis strains with natural SbV resistance induce a significant interferon response in macrophages, accompanied by overexpression of the IDO1 / IL4I1 - Kyn - AHR pathways and SOD2 , associated with immune homeostasis and regulation of microbicidal activity. Homeostatic regulation by the IDO1 / IL4I1 - Kyn - AHR pathways, induced in macrophages by infection with naturally SbV-resistant strains of L. (V . ) panamensis , prevails despite significant modulation of macrophage activation by antimony exposure. Antimony treatment promotes a more anti-inflammatory (M-MØ) profile in macrophages infected with naturally resistant L. (V . ) panamensis strains, while macrophages infected with sensitive strains maintain a more proinflammatory profile (GM-MØ). Infection with the zym 2.3 strains in the presence of SbV leads to downregulation of specific macrophage transporter genes, supporting the capacity of these naturally SbV-resistant parasites to elicit macrophage responses that enable antimony resistance.
Read full abstract