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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE55664 | GEO | 2014/03/07

SECONDARY ACCESSION(S): PRJNA240325

REPOSITORIES: GEO

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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

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).

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

2015-02-01 | GSE63931 | GEO

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

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

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

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Characterization of differentially abundant proteins among Leishmania (Viannia) braziliensis strains isolated from atypical or typical lesions

Project description:Leishmania (Viannia) braziliensis is the main etiological agent of cutaneous and mucocutaneous leishmaniasis in Latin America. Reports have described non-ulcerated atypical tegumentary leishmaniasis cases caused by L. braziliensis in several regions of the world, including in patients from the Xacriabá Indigenous reserve, in São João das Missões/Minas Gerais - Brazil. Parasites isolated from these atypical clinical lesions have previously been found to be resistant to antimony-based therapeutics. In the present study, proteins displaying differential abundance in 2 strains of L. braziliensis isolated from patients with atypical lesions compared with 4 strains isolated from patients with typical lesions were identified using a quantitative proteomics approach based on tandem mass tag labeling (TMT) and mass spectrometry. A total of 532 (p value <0.05) differentially abundant proteins were identified (298 up-regulated and 234 down-regulated) in strains from atypical lesions compared to strains from typical lesions. We observed a variety of proteins with differential abundance among the studied strains. Prominent positively regulated in atypical strains included proteins which may confer a greater survival inside the macrophage, proteins related to resistance to antimony and higher peroxidase activity. Also were identified proteins suggest as new drug and vaccines target. Our data contribute to characterization of these intriguing L. braziliensis strains, and sheds new light on ACL cases has been associated with therapeutic failures.

2022-02-11 | PXD029995 | Pride

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

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

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