Identification of immune mechanisms associated with the high rate of relapse in patient with visceral leishmaniasis and HIV co infection
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PROVIDER: EGAS00001003465 | EGA |
REPOSITORIES: EGA
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Project description:RNA-seq transcriptomics of whole blood samples from longitudinal follow-up of a cohort of visceral leishmaniasis (VL) patients with and without HIV coinfection, from active disease through apparent cure and potential relapse. Analysis will identify potential correlates of relapse to identify immune mechanisms underlying the high rate of relapse in HIV/VL coinfection. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ .
| EGAD00001008361 | EGA
Project description:Leishmania is an intracellular protozoan parasite and the etiological agent of a vector-borne disease known as leishmaniasis. This neglected tropical disease exhibits high morbidity and mortality. It is endemic in 97 countries and 700.000–1.000.000 new cases are estimated to occur each year. Leishmania-HIV co-infection has been an emergent public health problem in the last twenty years and has been reported in 35 endemic countries. HIV-infected people are especially vulnerable to visceral leishmaniasis (VL), and VL accelerates HIV replication and advancement to AIDS. In the context of HIV co-infection, the challenges associated with VL disease management are very significant. Disease presentation is often atypical and therapeutical responses are limited with recurrent relapses. A better understanding of the disease and also new biomarkers for infection detection, treatment prognosis and relapse are needed. Extracellular Vesicles (EVs), are considered a resource with great potential for generating a higher understanding of complex biological processes and also as a potential source of biomarkers. To evaluate the potential of plasma EVs in the context of VL and to find new possible molecules of interest for disease management in the context of HIV/VL coinfection, EVs were recovered from the plasma of an HIV+VL+ patient over a two-year period, and compared to age and sex-matched HIV and HIV-VL- controls. The approach selected for plasma EVs recovery was Size-Exclusion Chromatography followed by fraction selection using common EVs markers and proteomic analysis of fractions of interest by MS. The proteomic analysis performed confirmed the identification of common EVs biomarkers. The capacity to detect Leishmania proteins was limited with no identifications with more than one UP existed. Moreover no Leishmania protein identification was common between time points. Concernng human proteins, several proteins were detected with distinct abundance in the patient compared to both control groups. Using GO approach, the proteins were associated with specific biological processes, like MHC-I that provide a complementary overview of the patient immunological condition. Among the proteins detected, we highlighted the Macrophage receptor with collagenous structure (MARCO). This protein was detected in the patient in 4 out of 5 time points. Significantly, MARCO was also detected in plasma EVs from 5 other VL patients that were analysed. The presence of MARCO in the plasma EVs preparations was also confirmed by Western Blot. In conclusion, it was demonstrated that EVs analysis in the context of VL can contribute to understand the ongoing pathological process. Moreover, these EV are a source of possible biomarkers for VL monitoring. MARCO was a protein of interest being only identified in the VL patients. Ultimately, further studies need to be performed to generate a critical mass of data on EVs in the context of this and other infections to generate improvements in the clinical management of these vulnerable populations.
2025-07-07 | PXD049001 | Pride
Project description:Among the most central questions in Leishmania research is why some species remain in the skin dermis at the site of infection by the sand fly vector whereas other species migrate to visceral organs where they cause fatal visceral leishmaniasis. Although L. donovani is the species typically responsible for visceral leishmaniasis, an atypical L. donovani strain is the etiologic agent for cutaneous leishmaniasis in Sri Lanka. To identify molecular determinants for visceral disease, we have analysed the phenotype and genotype of two L. donovani clinical isolates from Sri Lanka where one isolate was derived from a cutaneous leishmaniasis patient (CL) and the other from a visceral leishmaniasis patient (VL). These isolates cause dramatically different pathology when introduced into mice; notably the CL isolate has lost the ability to survive in visceral organs while the VL isolate was highly virulent in visceral organs of BALB/c mice. Whole genome sequencing of the CL and VL isolates revealed that these genomes were very similar as there were no gene deletions and few individual gene amplifications. Indels resulting in frame shifts and loss/gain of stop codons resulted in 13 distinct pseudogenes present in each of the CL and VL isolates. There were 154 non-synonymous SNPs specific to the CL isolate and 193 non-synonymous SNPs specific to the VL isolate. Genome wide gene expression analysis revealed several transcript level differences, including the A2 virulence gene resulting in higher expression of A2 proteins in the VL isolate than in the CL isolate. Genotypic variations relevant to pathology and tropism in Leishmania can be interrogated by reverse genetics. Experimentally increasing A2 expression in the CL isolate through gene transfer significantly increased it’s ability to survive in the spleen of BALB/c mice and conversely, down-regulating A2 expression in the VL isolate abrogated attenuated its survival in BALB/c mice. These observations reveal that there are relatively few genetic differences between the CL and VL isolates apart from the A2 genes, but collectively these have profound effects on human disease and experimentally infected mice.
2013-12-31 | GSE48475 | GEO
Project description:Among the most central questions in Leishmania research is why some species remain in the skin dermis at the site of infection by the sand fly vector whereas other species migrate to visceral organs where they cause fatal visceral leishmaniasis. Although L. donovani is the species typically responsible for visceral leishmaniasis, an atypical L. donovani strain is the etiologic agent for cutaneous leishmaniasis in Sri Lanka. To identify molecular determinants for visceral disease, we have analysed the phenotype and genotype of two L. donovani clinical isolates from Sri Lanka where one isolate was derived from a cutaneous leishmaniasis patient (CL) and the other from a visceral leishmaniasis patient (VL). These isolates cause dramatically different pathology when introduced into mice; notably the CL isolate has lost the ability to survive in visceral organs while the VL isolate was highly virulent in visceral organs of BALB/c mice. Whole genome sequencing of the CL and VL isolates revealed that these genomes were very similar as there were no gene deletions and few individual gene amplifications. Indels resulting in frame shifts and loss/gain of stop codons resulted in 13 distinct pseudogenes present in each of the CL and VL isolates. There were 154 non-synonymous SNPs specific to the CL isolate and 193 non-synonymous SNPs specific to the VL isolate. Genome wide gene expression analysis revealed several transcript level differences, including the A2 virulence gene resulting in higher expression of A2 proteins in the VL isolate than in the CL isolate. Genotypic variations relevant to pathology and tropism in Leishmania can be interrogated by reverse genetics. Experimentally increasing A2 expression in the CL isolate through gene transfer significantly increased itM-bM-^@M-^Ys ability to survive in the spleen of BALB/c mice and conversely, down-regulating A2 expression in the VL isolate abrogated attenuated its survival in BALB/c mice. These observations reveal that there are relatively few genetic differences between the CL and VL isolates apart from the A2 genes, but collectively these have profound effects on human disease and experimentally infected mice. 6 Samples in total, 3 each from VL and CL causing isolates were analyzed by Splice Leader RNASeq. These three samples from each of the isolates were grown to form one of the following three lifestages, Promastigotes, Macrophage derived Amastigotes, Axenic Amastigotes.
2013-12-31 | E-GEOD-48475 | biostudies-arrayexpress
Project description:Visceral leishmaniasis (VL), the most severe form of leishmaniasis, lacks standardized and validated early predictors for cure and relapse, which is especially important for individuals at high-risk. Here, we searched for protein biomarkers in plasma extracellular vesicles (EVs). EVs from patients with active VL (n=12) and patients at post-treatment intervals (1, 3, and 6 months; n=12 per time interval) were analysed by tandem mass spectrometry coupled to liquid chromatography (LC-MS/MS) to characterize their proteomic profiles. Six candidate biomarkers were further tested by ELISA using total plasma. The comparison of the protein profiles of plasma EVs identified 132 human proteins differentially abundant in active VL compared to successfully cured patients, with 64 upregulated and 68 downregulated proteins in VL. Additionally, the analysis highlighted pathogenic mechanisms associated with VL and pathways associated to effective cure. Levels of SAA, and ITGB1 proteins showed a differential expression when analyzed in total plasma, emerging as promising easy-to-measure biomarkers for patients management. Remarkably, proteins from Leishmania spp. were identified in the EV samples, highlighting a novel source of parasite-derived biomarkers in human samples. Plasma EVs contain protein biomarkers to monitor VL treatment success, with some of them detectable using total plasma at 1 month after treatment. This study also provides a proteomic landscape of plasma derived EVs involved in VL, offering insights into disease pathogenesis.
2025-08-27 | PXD060604 | Pride
Project description:To ascertain which molecular pathways underlying the pathogenesis of human visceral leishmaniasis (VL) caused by the protozoan parasite Leishmania infantum, we performed modular co-expression gene networks analysis using CEMiTool R package and the transcriptional profile of whole blood samples from patients diagnosed with active VL compared to VL-treated condition (cured patients) and to healthy control samples.
2018-01-25 | E-MTAB-6137 | biostudies-arrayexpress
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.
2022-06-04 | GSE205452 | GEO
Project description:To ascertain which genes are involved in pathogenesis of human visceral leishmaniasis (VL) caused by the protozoan parasite Leishmania infantum, we investigated the transcriptional profile of whole blood samples from patients diagnosed with active VL compared to healthy control samples.
2016-11-16 | E-MTAB-4902 | biostudies-arrayexpress
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.
2020-08-06 | E-MTAB-8818 | biostudies-arrayexpress
Project description:To ascertain which genes are involved in the outcome of Leishmania infantum infections and immunopathology of human visceral leishmaniasis (VL), we investigated the transcriptional profile of whole blood samples from patients during active VL compared to the same patients 180 days after being treated, when they were considered clinically cured. Also, we compared VL transcriptional profile to asymptomatic individuals (positive serology for Leishmania, but without clinical signs of disease) and healthy uninfected control samples.
2022-03-10 | E-MTAB-11047 | biostudies-arrayexpress