Senescence-related genes are associated with the immunopathology signature of American Tegumentary Leishmaniasis lesions and may predict progression to mucosal leishmaniasis.

Autor:	Fantecelle CH; Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Brazil., Polaco Covre L; Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Brazil.; Division of Medicine, University College London, UK., Lopes PO; Núcleo de Biotecnologia, Universidade Federal do Espírito Santo, Brazil., Sarmento IV; Núcleo de Biotecnologia, Universidade Federal do Espírito Santo, Brazil., Decote-Ricardo D; Departamento de Veterinária, Universidade Federal Rural do Rio de Janeiro, Rio de Janeiro, Brazil., Geraldo Freire de Lima C; Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil., de Matos Guedes HL; Instituto de Microbiologia Professor Paulo de Goes, Universidade Federal do Rio de Janeiro, Brazil.; Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Brazil., Pimentel MIF; Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Brazil., Conceição-Silva F; Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Brazil., Maretti-Mira AC; USC Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA., Borges VM; Instituto Gonçalo Muniz, Fundação Oswaldo Cruz, Brazil., Pedreira de Carvalho L; Laboratório de Pesquisas Clínicas do Instituto Gonçalo Muniz, Fundação Oswaldo Cruz, Brazil., de Carvalho EM; Laboratório de Pesquisas Clínicas do Instituto Gonçalo Muniz, Fundação Oswaldo Cruz, Brazil., Mosser D; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, USA., Falqueto A; Departamento de Medicina Social, Universidade Federal do Espírito Santo, Brazil., Akbar AN; Division of Medicine, University College London, UK., Gomes DCO; Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Brazil.; Núcleo de Biotecnologia, Universidade Federal do Espírito Santo, Brazil.
Jazyk:	angličtina
Zdroj:	Clinical and experimental immunology [Clin Exp Immunol] 2024 Oct 21. Date of Electronic Publication: 2024 Oct 21.
DOI:	10.1093/cei/uxae088
Abstrakt:	The American Tegumentary Leishmaniasis (ATL) is caused by protozoans of the genus Leishmania and varies from mild localized cutaneous leishmaniasis (LCL) form to more severe manifestations such as the diffuse cutaneous leishmaniasis (DCL) form and the mucosal leishmaniasis (ML) form. Previously, we demonstrated the accumulation of senescent cells in skin lesions of patients with LCL. Moreover, lesional transcriptomic analyses revealed a robust co-induction of senescence and pro-inflammatory gene signatures, highlighting the critical role of senescent T cells in orchestrating pathology. In this work we hypothesized that senescent cells might operate differently among the ATL spectrum, potentially influencing immunopathological mechanisms and clinical outcome. We analysed previously published RNA-Seq datasets of skin biopsies of healthy subjects and lesional skin from DCL patients, LCL patients and LCL patients that, after treatment, progressed to mucosal leishmaniasis (MLP). Our findings demonstrate a robust presence of a CD8 T cell signature associated with both LCL and MLP lesions. Moreover, both inflammatory and cytotoxic signatures were significantly upregulated, showing a strong increase in MLP and LCL groups, but not DCL. The senescence signature was elevated between LCL and MLP groups, representing the only distinguishable signature of immunopathology between them. Interestingly, our analyses further revealed the senescence signature's capacity to predict progression from LCL to mucosal forms, which was not observed with other signatures. Both the senescence-signature score and specific senescence-associated genes demonstrated an increased capacity to predict mucosal progression, with correct predictions exceeding 97% of cases. Collectively, our findings contribute to a comprehensive understanding of immunosenescence in ATL and suggest that senescence may represent the latest and most important signature of the immunopathogenisis. This highlights its potential value in predicting disease severity. (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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