Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Variable gene expression and parasite load predict treatment outcome in cutaneous leishmaniasis

ABSTRACT: Patients infected with Leishmania braziliensis develop chronic lesions that often fail to respond to treatment. To determine whether genes whose expression is highly variable in lesions might influence disease outcome, we obtained biopsies of lesions from patients prior to drug treatment, performed transcriptomic profiling, and identified highly variable genes whose expression correlated with treatment outcome. Amongst the most variable genes were components of the cytolytic pathway, the expression of which appeared to be driven by parasite load in the skin. We demonstrated that treatment failure can be directly linked to the cytolytic pathway activated during infection. Using this host-pathogen biomarker profile, we show that treatment outcome can be predicted before the start of treatment. These findings not only raise the possibility of point-of-care diagnostic screening to identify patients at high risk of treatment failure and provide a rationale for a precision medicine approach to drug selection in cutaneous leishmaniasis, but more broadly also demonstrate the value of identifying genes of high variability in other diseases to better understand and predict diverse clinical outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE127831 | GEO | 2019/07/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Human transcriptome pattern of primary cutaneous lesions from patients with localized cutaneous leishmaniasis and mucosal leishmaniasis

Project description:We evaluated the trancriptome of primary cutaneous leisions caused by infection with Leishmania braziliensis. mRNA-seq technique was used to study the trancriptome of both host and parasite. A total of 10 samples was obtained from primary skin ulcers of two extreme clinical forms of American tegumentary leishmaniasis: (i) individuals that after antimonial treatment cured completely (localized cutaneous leishmaniasis - LCL, n=5) and (ii) individuals that developed mucosal lesions in naso and oropharynx areas long after initial healing of the cutaneous lesion (mucosal leishmaniasis - ML, n=5). The sequencing generated an average of 13+ 5 million reads per samples. The reads were aligned to Homo sapiens (USCS - hg19) and to Leishmania braziliensis (Wellcome Trust Sanger Institute - V2_29072008) genomes. Approximately, 15,000 human genes could be detected in the samples. Low amount of L. braziliensis reads did not allow the evaluation of parasite gene expression. LCL and ML samples showed different patterns of gene expression, indicating a more robust immune response in LCL individuals. In summary, this study demonstrated that next-generation sequencing can be used for identification of potentially important biological pathways and drug targets in the host-response to L. braziliensis infection and for characterization of a gene expression signature that could be used to predict the disease outcome. Moreover, we also showed the ability of this technique in, simultaneously, sequence host and pathogen mRNA. Examination of 10 fragments of cutaneous lesions: 5 from localized cutaneous leishmaniasis patients and 5 from mucosal leishmaniasis patients.

2012-10-24 | E-GEOD-33601 | biostudies-arrayexpress

Multi-omic profiling of cutaneous leishmaniasis infections reveals microbiota-driven mechanisms underlying disease severity

Project description:Leishmania braziliensis infection results in inflammation and skin injury, with highly variable and unpredictable clinical outcomes. Here, we investigated the potential impact of microbiota on infection-induced inflammatory responses and disease resolution by conducting an integrated analysis of the skin microbiome and host transcriptome on a cohort of 62 L. braziliensis-infected patients. We found that overall bacterial burden and microbiome configurations dominated with Staphylococcus spp. were associated with delayed healing and enhanced inflammatory responses, especially by IL-1 family members. Dual RNA-seq of human lesions revealed that high lesional S. aureus transcript abundance was associated with delayed healing and increased expression of IL-1β. This cytokine was critical for modulating disease outcome in L. braziliensis-infected mice colonized with S. aureus, as its neutralization reduced pathology and inflammation. These results implicate the microbiome in cutaneous leishmaniasis disease outcomes in humans and suggest host-directed therapies to mitigate the inflammatory consequences.

2023-07-27 | GSE214397 | GEO

Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-g signature

Project description:Cutaneous leishmaniasis is a localized infection controlled by CD4+ T cells that produce IFN-g within lesions. Phagocytic cells recruited to lesions, such as monocytes, are then exposed to IFN-g which triggers their ability to kill the intracellular parasites. Consistent with this, a transcriptional analysis of lesions from patients identified the presence of a strong interferon stimulated gene (ISG) signature. To determine what systemic responses are occurring that might influence the disease, we performed RNA sequencing (RNA-seq) on the blood of L. braziliensis-infected patients, as well as healthy controls. Functional enrichment analysis identified a transcriptional ISG signature as the dominant response in the blood of patients. An increase in monocytes and macrophages in the blood, estimated from our RNA-seq dataset, was positively correlated with this ISG signature. Consistent with this result, patients had circulating IFN-g in their serum. A cytotoxicity signature, which is a dominant feature in the lesions, was also found in the blood and correlated with an increased abundance of cytolytic cells. Thus, two transcriptional signatures present in lesions were found systemically, although with a substantially reduced number of differentially expressed genes (DEGs). Finally, we found that the number of DEGs and ISGs in leishmaniasis was similar to tuberculosis – another localized infection – but significantly less than observed in malaria. In contrast, the cytolytic signature and increased cytolytic cell abundance was not found in tuberculosis or malaria. Our results indicate that systemic signatures can reflect what is occurring in leishmanial lesions. Furthermore, the presence of an ISG signature in blood monocytes and macrophages suggests that when these cells enter lesions they may already be primed to control the parasites.

2021-03-23 | GSE162760 | GEO

Defining the transcriptional signature of healing and non-healing lesions during murine cutaneous leishmaniasis

Project description:Leishmaniasis is a group of diseases caused by parasites of the genus Leishmania that affects millions of people worldwide. The disease outcome is determined by both the parasite species and the host's immune response. Leishmania major infection causes a localized cutaneous lesion in patients and has been widely used to study the development of T cell responses in mice. L. major infected C57BL/6 mice are resistant to infection due to the development of Th1 responses, whereas BALB/c mice develop a Th2 response resulting in disease susceptibility and failure to control parasite replication. However, these disparate host phenotypes are not observed with all Leishmania species. For example, during L. braziliensis infection both BALB/c and C57BL/6 mice are resistant. In order to better understand the host genetic basis underlying disease susceptibility in vivo, we performed a whole genome transcriptional analysis from skin lesions of BALB/c and C57BL/6 mice infected intradermally for 4 weeks with either L. braziliensis or L. major.

2019-02-19 | GSE56029 | GEO

Human transcriptome pattern of primary cutaneous lesions from patients with localized cutaneous leishmaniasis and mucosal leishmaniasis

2012-10-24 | GSE33601 | GEO

CD8 T cells induce perforin-dependent pathology in Leishmania braziliensis infection

Project description:The mechanisms that mediate immunopathologic responses in infectious diseases are often less well understood than how the pathogens are controlled. Here, we have investigated what causes increased pathology following infection with the protozoan parasite, Leishmania braziliensis. We focused on CD8 T cells since their presence in leishmanial lesions has been correlated with increased disease. By adoptively transferring CD8 T cells to L. braziliensis infected RAG mice, we found that unregulated CD8 T cells promote severe pathology at the infection site, as well as the development of metastatic lesions in other skin sites. In mice with severe pathology, we visualized CD8 T cells degranulating and lysing L. braziliensis infected cells, and in parallel studies with L. braziliensis patients we confirmed that CD8 T cells within lesions exhibit a cytolytic phenotype. We found that perforin deficient CD8 T cells failed to induce disease, indicating that the increased disease induced by CD8 T cells was due perforin-dependent cytotoxicity. In contrast, although we found that CD8 T cells made both IFN-γ and IL-17, neither of these cytokines is required for the development of pathology. Thus, we show for the first time that immunopathology in leishmaniasis can be mediated by cytolytic CD8 T cells. Twelve skin biopsy samples were analyzed, including 2 normal skin biopsies obtained from patients in N. America, and 10 skin biosies obtained from Leishmania brazilensis infected patients presenting at the Corte de Pedra Health Post in Corte de Pedra, Bahia, Brazil

2013-07-08 | E-GEOD-43880 | biostudies-arrayexpress

CD8 T cells induce perforin-dependent pathology in Leishmania braziliensis infection

2013-07-08 | GSE43880 | GEO

Neutrophil-mediated hypoxia drives pathogenic CD8 T cell responses in cutaneous leishmaniasis

Project description:Cutaneous leishmaniasis caused by Leishmania parasites exhibits a wide range of clinical manifestations. Although parasites influence disease severity, cytolytic CD8 T cell responses mediate disease. While these responses originate in the lymph node, we found that expression of the cytolytic effector molecule granzyme B was restricted to lesional CD8 T cells in Leishmania-infected mice, suggesting that local cues within inflamed skin induced cytolytic function. Expression of Blimp-1 (Prdm1), a transcription factor necessary for cytolytic CD8 T cell differentiation, was driven by hypoxia within the inflamed skin. Hypoxia was further enhanced by the recruitment of neutrophils that consumed oxygen to produce reactive oxygen species and ultimately increased the hypoxic state and granzyme B expression in CD8 T cells. Importantly, lesions from cutaneous leishmaniasis patients exhibited hypoxia transcription signatures that correlated with the presence of neutrophils. Thus, targeting hypoxia-driven signals that support local differentiation of cytolytic CD8 T cells may improve the prognosis for patients with cutaneous leishmaniasis, as well as other inflammatory skin diseases where cytolytic CD8 T cells contribute to pathogenesis.

2024-04-29 | GSE193005 | GEO

Transcription profiling of cutaneous lesions caused by Leishmania braziliensis and normal skin.

Project description:This study was carried out to evaluate the changes that occur in the skin after the development of cutaneous leishmaniasis, aiming at a comprehensive understanding of immune pathways and biological functions activated in lesions caused by L. braziliensis. This analysis was conducted on 8 skin ulcers from patients infected with L. braziliensis. The patients selected for the gene expression analysis had recent L. braziliensis infection that had not yet been treated. 8 controls samples are skin biopsies from healthy donors (non-infected).

2015-02-01 | E-GEOD-63931 | biostudies-arrayexpress

Genomic profiling of human Leishmania braziliensis lesions identifies transcriptional modules associated with cutaneous immunopathology

Project description:The host immune response plays a critical role not only in protection from human leishmaniasis, but also in promoting disease severity. Although candidate gene approaches in mouse models of leishmaniasis have been extremely informative, a global understanding of the immune pathways active in lesions from human patients is lacking. To address this issue, genome-wide transcriptional profiling of Leishmania braziliensis-infected cutaneous lesions and normal skin controls was carried out. A signature of the L. braziliensis skin lesion was defined that includes over 2,000 differentially regulated genes. Pathway-level analysis of this transcriptional response revealed key biological pathways, as well as specific genes, associated with cutaneous pathology, generating a testable 'metapathway' model of immune-driven lesion pathology, and providing new insights for treatment of human leishmaniasis. Thirty-five skin biopsies were analyzed, including 10 normal skin biopsies (2 from North America and 8 from non-endemic area in Brazil), and 25 skin lesion biopsies (8 early cutaneous lesions, 17 late cutaneous lesions) obtained from Leishmania brazilensis-infected patients presenting at the Corte de Pedra Health Post in Corte de Pedra, Bahia, Brazil.

2014-03-07 | E-GEOD-55664 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data