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

ABSTRACT: 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-α+ 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE236962 | GEO | 2023/10/24

REPOSITORIES: GEO

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Project description:Leishmania (L) are intracellular protozoan parasites which are able to survive and replicate within the harsh and potentially hostile phago-lysosomal environment of mammalian mononuclear phagocytes. A complex interplay then takes place between the macrophage (MM-NM-&) striving to eliminate the pathogen and the parasite struggling for its own survival. To investigate, at the transcriptional level, this host-parasite conflict in the context of monocyte-derived human MM-NM-&s (MDM) infection by L. major metacyclic promastigotes, the quantitative technique of serial analysis of gene expression (SAGE) was used. After extracting mRNA from resting human MM-NM-&s, Leishmania-infected human MM-NM-&s and L. major parasites, three SAGE libraries were constructed and sequenced generating up to 28,173; 57,514 and 33,906 tags respectively (corresponding to 12,946; 23,442 and 9,530 unique tags). Using computational data analysis and direct comparison to 394,059 publicly available experimental human tags, the parasite and the host cell transcriptomes were then simultaneously characterized from the mixed cellular extract, allowing to confidently discriminate host from parasite transcripts. This procedure led us to reliably assign 3,814 tags to MM-NM-&sM-bM-^@M-^Y and 3,666 tags to L. major parasitesM-bM-^@M-^Y transcripts. We focused on those, showing significant changes in their expression that are likely to be relevant to the pathogenesis of parasite infection: (i) human MM-NM-&s genes, belonging to key immune response proteins (i.e. IFNM-NM-3 pathway, S100 and chemokine families) and (ii) a group of Leishmania genes showing a preferential expression at the intra-cellular developing stage of the parasite. Dual SAGE transcriptome analysis provided a useful, powerful and accurate approach to discriminate between genes of human or parasitic origin in Leishmania-infected human MM-NM-&s. The findings presented in this work suggest that the Leishmania parasite is modulating key transcripts in the human MM-NM-&s that may be beneficial for its establishment and survival and provided an overview of gene expression at two developmental stages of the parasite, namely metacyclic promastigotes and intracellular amastigotes, indicating a broad difference between their transcriptomic profiles. Finally, our reported set of expressed genes could deserve future rounds of data mining and gene annotation. Keywords: Leishmania major, Human macrophages, in vitro, infection, transcriptome, SAGE Human monocyte derived macrophages (MDM) from four healthy donors were infected in vitro for 24 hours with metacyclic Leishmania major parasites (ratio 1:5) and the pool was used to construct SAGE library. Non infected MDM from the same donors and from metacyclic Leishmania major parasites were used to construct the two controls' SAGE libraries.

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

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