The b-carboline harmine is an immunomodulator in cutaneous leishmaniasis favoring the balance towards a protective immune response

Here, we investigated the impact of synthetic b-carboline harmine (ACB1801), on the immune response and pathology resulting from infection with a drug-resistant Leishmania major strain causing non-healing cutaneous lesion. Exposure to ACB1801 impacted only slightly parasite viability and parasite burden in host macrophages in vitro. However, it significantly increased MHC-II and co stimulatory molecules expression on infected DCs, suggesting enhanced immune response. Accordingly, ACB1801 monotherapy significantly decreased lesion development and parasite burden in Leishmania infected C57BL/6 mice, with similar efficacy than the widely used Amphotericin B therapy. ACB1801 impact on the immune response was validated by transcriptomics analysis showing enrichment of TNF-a, IFN-g and MHC-II Ag presentation signatures in the draining lymph nodes of treated mice. Increased frequency of protective CD4+IFN-g+TNF-a+ T cells and reduced suppressive IL-10+FoxP3- T cells was observed by flow cytometry. ACB1801 was further shown to act via the downregulation of Aryl hydroxyl receptor (AhR) signaling, decreasing immunosuppressive cytokines. Thus, these results suggest a potential use for ACB1801 alone or in combination therapy. Overall design: C57BL/6 mice were injected with 2x105 LmSd metacyclic promastigotes into the ear dermis (i.d.). The treatments with ACB1801 or vehicle were started at day 12 post infection for 10 consecutive days. Draining lymph nodes were recovered in RLT plus buffer, homogenized using tissue lyzer. mRNA was extracted using Qiagen RNAeasy mini kit. Contralateral LNs were used as non-infected controls.