Senescence-related genes are associated with the immunopathology signature of american tegumentary leishmaniasis lesions and may predict progression to mucosal leishmaniasis

Universidade Federal do Espírito Santo. Centro de Ciências da Saúde. Departamento de Medicina Social. Núcleo de Doenças Infecciosas. Vitória, ES, Brasil.
Universidade Federal do Espírito Santo. Centro de Ciências da Saúde. Departamento de Medicina Social. Núcleo de Doenças Infecciosas. Vitória, ES, Brasil / University College London. Division of Medicine. London, UK.
Universidade Federal do Espírito Santo. Centro de Ciências da Saúde. Núcleo de Biotecnologia. Vitória, ES, Brasil.
Universidade Federal do Espírito Santo. Centro de Ciências da Saúde. Núcleo de Biotecnologia. Vitória, ES, Brasil.
Universidade Federal Rural do Rio de Janeiro. Instituto de Medicina Veterinária. Departamento de Microbiologia e Imunologia Veterinária. Seropédica, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Microbiologia Paulo de Góes. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunoparasitologia. Rio de Janeiro, RJ, Brasil.
University of Southern California. Keck School of Medicine. University of Southern California Research Center for Liver Diseases. Los Angeles, CA, USA.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Pesquisas Clínicas. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Pesquisas Clínicas. Salvador, BA, Brasil.
University of Maryland. Department of Cell Biology and Molecular Genetics. College Park, MD, USA.
Universidade Federal do Espírito Santo. Centro de Ciências da Saúde. Departamento de Medicina Social. Vitória, ES, Brasil.
University College London. Division of Medicine. London, UK.
Universidade Federal do Espírito Santo. Centro de Ciências da Saúde. Departamento de Medicina Social. Núcleo de Doenças Infecciosas. Vitória, ES, Brasil / Universidade Federal do Espírito Santo. Centro de Ciências da Saúde. Núcleo de Biotecnologia. Vitória, ES, Brasil.

Abstract

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.

Keywords in Portuguese

Leishmaniose tegumentar americana
Imunossenescência
Imunopatogênese
Biomarcador

Keywords

American tegumentary leishmaniasis
Immunosenescence
Immunopathogenesis
Biomarker

Publisher

Oxford University Press

Citation

CASTRO, Carlos Henrique Dettmann Fantecelle de et al. Senescence-related genes are associated with the immunopathology signature of american tegumentary leishmaniasis lesions and may predict progression to mucosal leishmaniasis. Clinical & Experimental Immunology, p. 1-32, 21 Oct. 2024.

DOI

10.1093/cei/uxae088

ISSN

0009-9104

Notes

Produção científica do Laboratório de Imunologia Clínica.
Produção científica do Laboratório de Imunoparasitologia.

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/66817

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