Interplay of human macrophage response and natural resistance ofL.(V.)panamensisto pentavalent antimony
Authors: Fernández Olga Lucía , Belew Ashton Trey , Rosales-Chilama Mariana , Sánchez-Hidalgo Andrea , Colmenares María , Saravia Nancy Gore , El-Sayed Najib M. 
Published: November 2024

ABSTRACTMacrophages are the principal host cells ofLeishmania 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 toex vivoinfection with clinical strains ofL. (V.) panamensisnaturally 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 responses and cytokine signaling by 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 homeostasis and microbicidal regulation, such as theIDO1/IL4I1-Kyn-AHRpathways and superoxide dismutase, and downregulation of transporters likeABCandAQP, 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 theex vivomacrophage 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 ofLeishmaniainfection and response to treatment.IMPORTANCEDrug 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 withLeishmania (Viannia) panamensisstrains 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.Graphical abstractClinical strains ofL. (V.) panamensisnaturally resistant or sensitive to antimonial drug (SbV) induce different profiles of human macrophage activation.L. (V.) panamensisstrains with natural SbV resistance induce a significant interferon response in macrophages, accompanied by overexpression of theIDO1/IL4I1-Kyn-AHRpathways andSOD2, associated with immune homeostasis and regulation of microbicidal activity.Homeostatic regulation by theIDO1/IL4I1-Kyn-AHRpathways, induced in macrophages by infection with naturally SbV-resistant strains ofL. (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 resistantL. (V.) panamensisstrains, 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