# Interplay of human macrophage response and natural resistance of infection by L. (V.) panamensis to pentavalent antimony

## TL;DR

This study shows how human macrophages respond differently to Leishmania parasites that are naturally resistant or sensitive to antimonial drugs, influencing infection and treatment outcomes.

## Contribution

The study reveals novel host macrophage responses linked to natural resistance of Leishmania parasites to antimonial drugs.

## Key findings

- Macrophages infected with resistant Leishmania strains show increased interferon and cytokine signaling.
- Resistant parasites induce anti-inflammatory pathways and alter transporter expression in macrophages.
- These responses persist even in the presence of antimonial drugs.

## 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.

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.