Role of tryptophan catabolism and AHR pathways in natural resistance of Leishmania (Viannia) panamensis to antimonial drug

Pentavalent antimony has been the first-line treatment for cutaneous leishmaniasis (CL) in South America for over four decades despite frequent treatment failure. Leishmania (Viannia) panamensis is the predominant causative agent of CL in Colombia. Previous investigations by our research team revealed that subpopulations of L. (V.) panamensis distinguished by their isoenzyme profiles display natural resistance (zymodeme 2.3) and sensitivity (zymodeme 2.2) to meglumine antimoniate (Sb) in vitro. We have also recently shown that CL caused by naturally resistant 2.3 strains present a significantly higher rate of treatment failure (63%) than CL caused by sensitive 2.2 strains (31%). Transcriptome-based sequencing analysis revealed that human macrophages infected with naturally resistant subpopulations of L. (V.) panamensis exhibited a significant induction of genes associated with the tryptophan catabolism and AHR pathways, important regulators of the proinflammatory and microbicidal response. These findings suggest that strains belonging to the naturally antimony-resistant subpopulation elicit differential modulation of the human macrophage response compared to the antimony- sensitive subpopulation. The gene products induced in host macrophages by naturally Sb-resistant and sensitive subpopulations of L. (V.) panamensis may enable the resistance phenotype as well as treatment failure, thereby constituting potential therapeutic targets. We hypothesize that the host cell response elicited by the infection with these distinct subpopulations of L. (V.) panamensis is a determinant of their natural resistance or sensitivity to pentavalent antimonial drugs. To evaluate this hypothesis, we will focus on the participation of the tryptophan catabolism and AHR pathways in the natural resistance of L. (V.) panamensis to antimonial drugs. We will take advantage of the two distinct subpopulations of L. (V.) panamensis exhibiting natural resistance or sensitivity to meglumine antimoniate to discern the participation of the host cell response in parasite susceptibility to antimonial drugs. To accomplish this, we will: i) determine the functional contribution of the IDO/Il4I1-Kyn-AHR pathways induced in primary human macrophages in natural resistance to antimonial drugs, and ii) identify the genes and interacting pathways influenced by the IDO/Il4I1-Kyn-AHR pathways that are involved in the distinct macrophage responses to naturally Sb-resistant and sensitive L. (V.) panamensis and antimony exposure. The ultimate goal of this project is to identify targetable pathways and gene products among those modulated in the macrophage by infection with natural antimony-resistant and sensitive parasites. The findings will contribute to the design and development of macrophage‐targeted therapeutic strategies and therapeutic approaches that optimize treatment based on the interplay of anti-parasitic treatment and host cell responses.