Senescence and Immunoregulation Constitute Distinct Immune Niches in the Immunopathogenesis of Localized and Diffuse Cutaneous Leishmaniasis. 2026.
Name: PAOLA DE OLIVEIRA LOPES
Publication date: 04/09/2026
Examining board:
Name |
Role |
|---|---|
| CLAUDIA IDA BRODSKYN | Examinador Externo |
| DANIEL CLAUDIO DE OLIVEIRA GOMES | Presidente |
| DJALMA DE SOUZA LIMA JUNIOR | Examinador Externo |
| ELDAMARIA DE VARGAS WOLFGRAMM DOS SANTOS | Examinador Interno |
| LUCIANA POLACO COVRE | Coorientador |
Pages
Summary: Cutaneous leishmaniasis comprises distinct clinical manifestations resulting from the interaction between the parasite and the host immune response. In localized cutaneous leishmaniasis (LCL), inflammatory and cytotoxic responses contribute to
parasite control but also participate in tissue damage. Recent evidence further indicates that this inflammatory environment is associated with immunosenescence, a phenomenon that may exacerbate the development of ulcerative lesions. In diffuse
cutaneous leishmaniasis (DCL), by contrast, the effector immune response is insufficient, and the lesional microenvironment favours parasite persistence. Despite advances in the characterisation of immune responses in these clinical forms, the
spatial organisation of cellular components and functional programmes within the lesions remains poorly understood. This thesis investigated the formation of immune niches implicated in the immunopathogenesis of cutaneous leishmaniasis using spatial
biology approaches, with a particular focus on microenvironments associated with cellular senescence in LCL and immune regulation in DCL. In lesions from patients with DCL, the analysis revealed the presence of niches characterised by intense
vacuolar parasitism within macrophages. These niches showed a close association with Treg cells and the production of heme oxygenase-1, a mediator with immunosuppressive functions. The spatial distribution of these regulatory cells and
mediators suggests their contribution to tissue permissiveness and to the maintenance of the high parasite burden characteristic of DCL. In LCL, biopsies from patient lesions revealed regions with widely distributed and heterogeneous transcriptional signatures associated with cellular senescence. These regions were enriched for signatures of the senescence-associated secretory phenotype (SASP), displayed increased expression of inflammatory mediators, and showed a spatial association with areas of high cytotoxic activity. Histopathological analyses further demonstrated that regions with a higher density of senescent cells also exhibited clear signs of tissue damage, including haemorrhage and apoptosis, as well as evidence of tissue remodelling, indicated by the presence of fibrosis. Taken together, these findings indicate that cellular senescence and immune regulation constitute distinct immune niches in the cutaneous forms of leishmaniasis and are closely associated with disease
immunopathogenesis. Understanding these niches expands the current model of cutaneous leishmaniasis immunopathogenesis and may help guide the development of therapeutic strategies capable of preserving antiparasitic responses while reducing
tissue damage.
