Caracterização abrangente de pequeno RNA em portadores de HTLV-1 assintomáticos e doentes, com ATLL e HAM/TSP

• Ano de defesa: 2017
• Autor(a) principal: Souza, Daniela Raguer Valadão de [UNIFESP]
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: HTLV-1; ATLL; HAM; TSP; smRNA; Second generation sequencing; Paraparesis, tropical spastic; Sequenciamento segunda geração; Paraparesia espástica tropical
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=5249700; https://repositorio.unifesp.br/handle/11600/50770

The Human T-lymphotropic virus type I (HTLV-I) is the causative agent of a spectrum of clinical manifestations, ranging from asymptomatic infection to a number of human disorders, most notably a malignant ATLL and a chronic progressive neuromyelopathy, termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Small non-coding RNAs (sRNAs) evolved to play important roles in virus-host interactions. In the present study, we used the massive parallel sequencing (MPS) approach to investigate the characteristic expression of sRNA during the development of ATLL and HAM/TSP in HTLV-1 infected patients and to identify known and new sRNA genes resident in peripheral blood mononuclear cells (PBMCs). In order to perform an unbiased sRNA profile, 44 samples from HTLV-1 infected individuals, previously known in terms of clonality and proviral load (PVL), were subjected for analysis. Participants were categorized into four groups: asymptomatic polyclonal (ACs-P, n = 8), asymptomatic monoclonal (ACs-M, n = 8), HAM / TSP patients (n = 16) and ATLL patients (n = 12). The analysis strategy involved the comparison of the group of ACs-P subjects with the other groups, namely (ACs-P vs ACs-M), (ACs-P vs HAM/TSP), and (ACs-P vs ATLL). In the ACs-P vs ACs-M group, only one miRNA (miRNA 33a-5p) was significantly down regulated (p <0.001). In the ACs-P vs. HAM / TSP group, 15 sRNAs were significantly deregulated (p <0.001) of which 11 were down regulated and 4 up-regulated. The top 5 most abundantly expressed sRNA were miRNAs 651, 151b, 154-3p, 18b-5p and 539-3p. In the ACs-P vs. ATLL group, 27 sRNAs were significantly deregulated (p <0.001). Of these, 16 were down regulated and 11 were up regulated. The top 5 most significantly and differentially expressed sRNAs were: miRNAs 577, 3194-5p, 4772-5p, 296-5p and 3934 -5p. Most of the miRNAs presented here are already described as involved in other oncological processes, however only miR-1 has already been related to HTLV-1 infection. Further analysis of the expression profile of these 4 groups revealed a characteristically unique and very significant expression profile in ATLL patients with acute leukemic form. The following 10 possible biomarkers are believed to play important role in progression of the disease to leukemic form: miRNAs 3200-3p, 4732-5p, 3688-3p, 3200-5p, 183- 5p, 144-5p, 296-5p, 451a, 577 and 193a-5p. Of these miRs, the miR-144/451 cluster is suggested to be closely involved in the pathogenesis of ATLL. Also, their high expression in acute ATLL can be used as a potential biomarker for the diagnosis of the disease. This study characterized the small RNA in the BPMCs from HTLV-1 patients in different clinical settings using MPS technology for the first time, which provides an opportunity for further understanding of sRNA regulation function during the course of HTLV-1 infection. The small RNA described here, might serve as biomarkers or therapeutic targets in the future.