Transcriptional signature of CD4+ T cells from visceral leishmaniasis patients
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE135965 | GEO | 2020/06/12
REPOSITORIES: GEO
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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: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:Transcriptional signature of CD4+ T cells from visceral leishmaniasis patients
| PRJNA560793 | ENA
Project description:In chronic infections, sustaining the CD4 T cell responses is crucial for pathogen clearance. The expression of inhibitory receptors such as LAG-3 or Lymphocyte activation gene 3 is usually associated with immune suppression and T cell exhaustion. However, LAG-3 also serves as an immune checkpoint molecule and is implicated in proliferation control and cell survival. In this study, we have utilized a mouse model of visceral leishmaniasis (VL), to characterize a subset of LAG-3- and CXCR5-expressing CD4 T cells. These LAG-3+CXCR5+PD-1lo/int CD4 T cells exist in naïve mice, they expand during VL, and are antigen specific. Importantly, the RNAseq analysis showed that these cells highly express gene signatures associated with self-renewal capacity, indicating that these cells might act as progenitors. Additionally, upon adoptive transfer into Rag1-/- mice followed by challenge with Leishmania donovani, these LAG-3+CXCR5+ PD-1lo/int CD4 T cells gave rise to different types of T effector and regulatory subsets, demonstrating their differentiation potential. These cells were also observed in mice infected with LCMV clone-13 and Heligmosomoides polygyrus bakeri. In summary, we propose that these LAG-3+CXCR5+ PD-1lo/int CD4 T cells that exhibit progenitor-like capacities could be implicated in maintaining CD4 T cell responses in chronic infections.
2024-02-13 | GSE255333 | GEO
Project description:Visceral leishmaniasis (VL) caused by Leishmania donovani and L. infantum is a potentially fatal disease. To date there are no registered vaccines for disease prevention despite the fact that several vaccines are in preclinical development. Thus, new strategies are needed to improve vaccine efficacy based on a better understanding of the mechanisms mediating protective immunity and mechanisms of host immune responses subversion by immunopathogenic components of Leishmania. In the present study, determination of the immune mechanisms related to infection or protective immune responses against VL using an experimental nanovaccine as a vaccine model was conducted through microarray analysis.
2019-11-19 | GSE134661 | GEO
Project description:Bulk RNA-sequencing was performed on CD4+ T cells isolated from the blood of visceral leishmaniasis patients (n = 12) and endemic controls (EC; n = 12). CD4+ T cells were obtained by magnetic-activated cell sorting (MACS). Alterations in the transcripts of T helper (Th) cells during infection were identified.
| EGAS00001004152 | EGA
Project description:Transcriptomic and immunopathology analysis on infection of mice with visceral leishmaniasis and a comparison of murine infection compared to hamster
2018-04-20 | GSE113376 | GEO
Project description:RNAseq of mouse liver and spleen samples infected with M. bovis treated with ambisome Liposomal amphotericin B (AmBisome) is a commonly used treatment for visceral leishmaniasis (VL), but is significantly less effective in the treatment of VL in East Africa, where the burden of disease is now greatest. Despite its widespread use, little is known of the mode of action of AmBisome. Here, we sought to examine the impact of AmBisome on tissue-specific transcriptomic changes following experimental infection with Leishmania donovani, in the two most clinically important tissues for treatment, the spleen and the liver. BALB/c mice infected with M. bovis BCG (an organism resistant to AmBisome treatment) were used to distinguish between direct effects of AmBisome and those that are secondary to parasite death using the RNAseq libraries generated to compare to previously published transcriptomic data of Leishmania donovani infected spleen and liver tissues treated with AmBisome. Our data indicate that the tissue response to AmBisome treatment is varied in different target organs and that full restoration of homeostasis is not achieved at parasitological cure. The pathways required to restore homeostasis deserve fuller attention in order to understand mechanisms associated with treatment failure and relapse and to promote more rapid restoration of immune competence.
2019-10-15 | GSE138825 | GEO
Project description:Visceral leishmaniasis (VL; Leishmania donovani) cases produce interferon- (IFN) and tumour necrosis factor (TNF) in response to soluble leishmanial antigen (SLA) in whole blood assays. These pro-inflammatory cytokines are crucial for activation of macrophages to kill L. donovani parasites. Detailed immunological studies comparing active with cured patients suggest that a balance exists between the pro-inflammatory cytokines TNF and IFN, and anti-inflammatory interleukin-10 (IL10). Our interest was to obtain a global understanding of the response to SLA in whole blood from active VL cases, and to determine what effect neutralising anti-IL10 would have on this response. Transcriptional profiles following SLA stimulation of whole blood from VL patients showed very few differentially expressed genes (DEGs), the majority belonging to a single network with TNF at the hub. In contrast, when anti-IL10 was added with SLA, hundreds of DEGs were observed, 65% belonging to a single network with TNF, IFNG, NFKBIA, IL6 and IL1B as hub genes in concert with a remarkable chemokine/cytokine storm. Our data demonstrate the singular impact of IL10 as a potent immune modulator in VL.
2021-03-31 | GSE146908 | GEO
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