Project description:Given the discontinuation of various first-line drugs for visceral leishmaniasis (VL), large-scale in vivo drug screening, establishment of a relapse model in rodents, immunophenotyping and transcriptomics were combined to study persistent infections and therapeutic failure. Double bioluminescent/fluorescent Leishmania infantum and L. donovani reporter lines enabled the identification of long-term hematopoietic stem cells (LT-HSC) as a niche with remarkably high parasite burdens, a feature confirmed for human hematopoietic stem cells (hHSPC). LT-HSC are more tolerant to antileishmanial drug action and serve as source of relapse. A unique transcriptional “StemLeish” signature in these cells was defined byupregulated TNF/NF-kB and RGS1/TGF-β/SMAD/SKIL signalling, and a downregulated oxidative burst.Cross-species analyses demonstrated significant overlap with human VL and HIV co-infected blood transcriptomes. In summary, the identification of LT-HSC as a drug- and oxidative stress-resistant niche,undergoing a conserved transcriptional reprogramming underlying Leishmania persistence and treatment failure, may open new therapeutic avenues for leishmaniasis.
Project description:Transcriptome analysis of intracellular amastigotes of clinical Leishmania infantum lines from therapeutic failure patients after infection of human macrophages
Project description:To investigate dendritic cells-Leishmania interaction, the transcriptional profile of bone marrow-derived dendritic cells (BMDCs) infected with Leishmania infantum or of cells exposed to chemically inactivated parasites was assessed
Project description:Leishmania RNA virus 1 (LRV1) is a double stranded RNA (dsRNA) virus found in some strains of the human protozoan parasite Leishmania, the causative agent of leishmaniasis, a neglected tropical disease. Interestingly, the presence of LRV1 inside Leishmania constitutes an important virulence factor which worsens leishmaniasis outcome in a type I interferon (type I IFN) dependent manner and contributes to treatment failure. Understanding how macrophages respond towards Leishmania alone or in combination with LRV1 as well as the role that type I IFNs may play during infection is fundamental to oversee new therapeutic strategies. In order to dissect the macrophage response towards infection, RNA Sequencing (RNA-Seq) was performed on murine wild-type (WT) bone marrow derived macrophages infected with Leishmania guyanensis (Lgy) devoid or not of LRV1 (LgyLRV1- and LgyLRV1+ respectively) or co-infected with LgyLRV1- and Lymphocytic choriomeningitis virus (LCMV) for 8 and 24 hours. Additionally, macrophages were treated with type I IFN (IFNα or IFNβ) after 6 hours of infection.
Project description:To ascertain which genes are involved in the outcome of Leishmania infantum infection and immunopathology of human visceral leishmaniasis (VL), we investigated the transcriptional profile of whole blood samples from patients diagnosed with active VL compared to asymptomatic individuals (positive serology for Leishmania, but without clinical signs of disease) and healthy control samples.
Project description:Leishmania RNA virus is an endosymbiotic virus of obligate intracellular Leishmania parasites. The presence of Leishmania RNA virus has been associated to metastatic leishmaniasis in hamsters and the failure of the first-line treatment in humans. This experiment aims to find the differences in the microRNA profile of bone-marrow derived macrophages infected with Leishmania RNA virus containing L.guyanensis or virus-free parasites.
Project description:Gene expression profiling to address the effects of infection with Leishmania infantum during distinct clinical outcomes as active visceral leishmaniasis (VL), remission of disease and asymptomatic infection.
