Leishmaniose Tegumentar Americana. Imunossenescência.
Predição. Biomarcador. Transcriptômica.
Name: CARLOS HENRIQUE DETTMANN FANTECELLE DE CASTRO
Publication date: 25/10/2024
Examining board:
Name |
Role |
|---|---|
| DANIEL CLAUDIO DE OLIVEIRA GOMES | Presidente |
| EDSON OLIVEIRA DELATORRE | Examinador Interno |
| HERBERT LEONEL DE MATOS GUEDES | Examinador Externo |
| JOÃO SANTANA DA SILVA | Examinador Externo |
| RODRIGO RIBEIRO RODRIGUES | Examinador Interno |
Summary: Cellular senescence is a phenomenon capable of affecting several cell types,
including cells of the immune system, termed immunosenescence. In this context, in
recent years our group have been demonstrating that this phenomenon has an
important role in the immunopathogenesis of Localized Cutaneous Leishmaniasis
(LCL). Nevertheless, LCL represents the less severe clinical form and is in the middle
of the spectrum of disease manifestations of the American Tegumentary
Leishmaniasis (ATL). On one side of this spectrum, the Diffuse Cutaneous (DCL) form
presents a regulatory response unable to eliminate the parasite. On the opposing end,
the Mucosal (ML) form of the disease shows a substantial increase in the production
of inflammatory and cytotoxic mediators. Given the importance of this phenomenon
and these different characteristics, this work had the goal of analysing the
transcriptional profile associated to cellular senescence in patients with DCL, LCL and
patients with LCL which progress to ML (MLP). First, we observed an increase in
expression of key senescence markers (ATM, Sestrin 2, p16, p21 e p38) and of the
senescence-associated secretory phenotype in patients with LCL¸ where these
features were associated with the increase in CD8 T EMRA cells. Next, when we
analysed the different forms of ATL, we observed that the groups LCL and MLP
showed an increase in genes of inflammation (IL-1, IL-6, IL-15, IFN-, TNF-),
cytotoxicity (Granzymes, Granulysin, Perforin, LAT, DAP-12 e ZAP70) and
senescence (ATF, CD57, Sestrin 2, p16, p21, p38, p52 e p53), which were reduced in
the DCL group. Furthermore, MLP patients showed an additional increase on the
senescence signature, which was the only signature able to predict the progression
from LCL to ML. Collectively, these results suggest that senescence may be the main
gene signature of the immunopathogenesis of these diseases, and the premature
induction of these phenomenon may be intimately related to the worsening observed
in these clinical forms.
