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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE193005 | GEO | 2024/04/29

REPOSITORIES: GEO

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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

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

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Project description:Cytolytic CD8+ T cells mediate immunopathology in cutaneous leishmaniasis without controlling parasites. Here, we identify factors involved in CD8+ T cell migration to the lesion that could be targeted to ameliorate disease severity. CCR5 was the most highly expressed chemokine receptor in patient lesions, and the high expression of CCL3 and CCL4, CCR5 ligands, was associated with delayed healing of lesions. To test the requirement for CCR5, Leishmania-infected Rag1-/- mice were reconstituted with CCR5-/- CD8+ T cells. We found that these mice developed smaller lesions accompanied by a reduction in CD8+ T cell numbers compared to controls. We confirmed these findings by showing that the inhibition of CCR5 with maraviroc, a selective inhibitor of CCR5, reduced lesion development without affecting the parasite burden. Together, these results reveal that CD8+ T cells migrate to leishmanial lesions in a CCR5-dependent manner and that blocking CCR5 prevents CD8+ T cell-mediated pathology.

2024-04-29 | GSE245292 | GEO

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2024-04-29 | GSE260729 | GEO

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

Comparative proteomic analysis of Leishmania parasite isolates obtained from visceral and cutaneous leishmaniases patients

Project description:As a vector-borne disease, leishmaniasis is caused by a parasitic protozoans of leishmania genus and transmitted by female Phlebotomine sandflies. Depending on the body location where immotile form of the parasite namely amastigote is proliferated, three main clinical forms as cutaneous, muco-cutaneous and visceral leishmaniases are defined. While manifestation of cutaneous leishmaniasis is skin lesions on the exposed part of the body, enlarged lymph nodes, spleen or liver along with fever, fatigue and weight loss are the symptoms of visceral leishmaniasis. The most dangerous form is visceral leishmaniasis since it may end up with fatalities if patients are not treated. The purpose of this study was to investigate the difference between the protein expression profiles of leishmania isolates obtained from visceral and cutaneous leishmaniasis patients. To compare two sample groups to each other genetically, L.infantum was chosen since it causes both visceral and cutaneous leishmaniasis. Additionally, another sample group as cutaneous leishmaniasis caused by L.tropica was included to make the comparison both intra- and interspecies level. For protein profiling, both gel-based and gel-free proteomic approaches were carried out. In brief, a total of 15 samples, 5 from each group, were separated on pI 3-10 2D-PAGE gel. Additionally, 9 of those 15 samples, 3 from each group, were analyzed according to qualitative shotgun proteomics method and differential proteins were determined by drawing venn diagram.

2022-01-14 | PXD016333 | Pride

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

2014-03-07 | GSE55664 | GEO

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2016-09-01 | E-MTAB-4413 | biostudies-arrayexpress

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2015-08-03 | GSE58369 | GEO

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