Tissue-specific transcriptomic changes associated with AmBisome treatment of mice with experimental visceral leishmaniasis [LV9]
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PROVIDER: PRJNA590983 | ENA |
REPOSITORIES: ENA
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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:Tissue-specific transcriptomic changes associated with AmBisome treatment of mice with experimental visceral leishmaniasis
| PRJNA577457 | ENA
Project description:Tissue and host species specific trasncriptional changes in models of experimental visceral leishmaniasis
| PRJNA450981 | ENA
Project description:Early Transcriptional Liver Signatures in Experimental Visceral Leishmaniasis
| PRJNA667926 | ENA
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:This study was designed to invesitgate changes in the transcriptional changes in CD4+ T cells from visceral leishmaniasis patients infected with L. donovani.
2020-06-12 | GSE135965 | 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
Project description:Background: Human visceral leishmaniasis, caused by infection with Leishmania donovani or L. infantum, is a potentially fatal disease affecting 50,000-90,000 people yearly in 75 disease endemic countries, with more than 20,000 deaths reported. Experimental models of infection play a major role in understanding parasite biology, host-pathogen interaction, disease pathogenesis, and parasite transmission. In addition, they have an essential role in the identification and pre-clinical evaluation of new drugs and vaccines. However, our understanding of these models remains fragmentary. Although the immune response to Leishmania donovani infection in mice has been extensively characterized, transcriptomic analysis capturing the tissue-specific evolution of disease has yet to be reported. Methods: We provide an analysis of the transcriptome of spleen, liver and peripheral blood of BALB/c mice infected with L. donovani. Where possible, we compare our data in murine experimental visceral leishmaniasis with transcriptomic data in the public domain obtained from the study of L. donovani-infected hamsters and patients with human visceral leishmaniasis. Digitised whole slide images showing the histopathology in spleen and liver are made available via a dedicated website, www.leishpathnet.org. Results: Our analysis confirms marked tissue-specific alterations in the transcriptome of infected mice over time and identifies previously unrecognized parallels and differences between murine, hamster and human responses to infection. We show commonality of interferon-regulated genes whilst confirming a greater activation of type 2 immune pathways in infected hamsters compared to mice. Cytokine genes and genes encoding immune checkpoints were markedly tissue specific and dynamic in their expression, and pathways focused on non-immune cells reflected tissue specific immunopathology. Our data also addresses the value of measuring peripheral blood transcriptomics as a potential window into underlying systemic disease. Conclusions: Our transcriptomic data, coupled with histopathologic analysis of the tissue response, provide an additional resource to underpin future mechanistic studies and to guide clinical research.
| S-EPMC6248268 | biostudies-literature