Assinatura transcricional da imunossenescência em lesões de pacientes com leishmaniose cutânea causada por Leishmania braziliensis

Abstract

Imunosenescence is a word used to describe multiple characteristics observed at the immune cells compartment. Recently, our group demonstrated that circulating senescent T and NK cells accumulate in patients with localized cutaneous leishmaniasis (LCL), a disease caused by parasites of the Leishmania genus. These populations with high inflammatory and cytotoxic activity were also found within cutaneous lesions of patients and correlated with disease severity. Given the importance of this phenomenon, this work aimed to analyze the expression profile of genes associated to senescence and the immunopathogenesis of LCL. For that, we reanalyzed RNA sequencing data of public domain, in which the gene expression of healthy skin biopsies is compared with skin lesion biopsies from patients infected with L. braziliensis. Our results demonstrate the presence of an extensive senescent phenotype on lesions of patients with LCL. This phenotype is dominated by alterations in genes associated to cell cycle control (increase of p16 and p21); signalling genes (increase of ATM and Sestrin 2); NK cell receptors (increase of genes from the KIR, KLR and NKp families); transcription factors (increase of ZEB2 and TBX21, decrease of FOXO genes); in addition to the increase on the majority of genes belonging to the senescence-associated secretory phenotype (SASP) and receptors of proinflammatory cytokines. We also demonstrated an increase in estimated relative frequencies of highly differentiated NK and CD8+ T (TEM and TEMRA) cell subsets which were positively correlated with the main genes of cytotoxicity (granzymes, perforin), proinflammatory response (IL-12R, IL-15, IL-15R, IL-18R, IL-1A, IL-1β, IL-2R, IFN-γ and TNF-α) or processes related to the induction and maintenance of senescence features (ATF, ATM, p16, KLRG1, Sestrin 2, TRAILR2, TRAILR3). On this work, we identified for the first time an imunosenescence transcriptional signature on lesions of patients with LCL, extrapolating our previous findings that indicate its role on the immunopathogenesis of this disease. Overall, this study improves our understanding of local and systemic immunity relating to LCL and provides a perspective for new therapeutic strategies