Banca de DEFESA: JÉSSICA LAÍS ALMEIDA DOS SANTOS
Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.DISCENTE : JÉSSICA LAÍS ALMEIDA DOS SANTOS
DATA : 16/12/2020
HORA: 13:00
LOCAL: Web conferência
TÍTULO:
HTLV-1 INFECTION AND HAM/TSP PROGRESSION: CONTRIBUTION OF HUMAN AND VIRAL MOLECULAR MARKERSPALAVRAS-CHAVES:
HTLV-1, HAM/TSP, SNPs, epitopes, virus, host
PÁGINAS: 120
GRANDE ÁREA: Ciências da Saúde
ÁREA: Saúde Coletiva
RESUMO:
Human T-cell lymphotropic virus type 1 (HTLV-1) is a sexually transmitted human retrovirus. Its main clinical manifestations are HTLV-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) and T-Cell Leukemia / Lymphoma of the Adult (ATLL). HAM/TSP is an inflammatory disorder of the central nervous system that can result in partial loss of lower limb movements. Although many events aspects that lead to the disease development are unclear, the host's immune response, especially the cellular response triggered by specific CD8+ T cells, is recognized as a crucial event. The objective of this work is to investigate molecular markers in the virus and in the host that may be related to the manifestation of the disease, mainly HAM/TSP. In Chapter I we have search for viral markers, with regard to the differential epitope presentation, for the different clinical profiles. We carried out a survey (Genbank) of 46 HTLV-1 complete genomes, and separated the coding regions of Tax, HBZ, p12, gp21 and gp46 proteins. Such gene regions were translated and evaluated for the presence of SNPs (Single Nucleotide Polymorphism). These SNPs were represented in AA sequences that were submitted to the IEDB (Immune Epitope Database Analysis Resource) to predict linear epitopes linking HLA-I molecules. It was possible to identify 7 “protein alleles” for the gp21 protein, 23 for gp46, 20 for HBZ, 13 for the Tax protein, and 15 for the p12 protein, all distributed among individuals ASS, fHAM/TSP (Familiar), sHAM/TSP (Sporadic) and ATLL. In prediction results, more than 15,741 epitopes were identified for p12, the lowest amount of predicted epitopes and more than 50,000 for Tax, with the highest amount of predicted epitopes. The p12 protein had the highest proportion of specific epitopes, also followed by the Tax protein. The HBZ protein had the lowest percentages in all specificity ranges. The results found for structural proteins gp46 and gp21 were similar. There was no specificity/exclusivity of HLA alleles among proteins, "protein alleles" and/or host clinical profiles. Each protein presented an HLA allele as being the most frequent among the “protein alleles”, with no similarity in this occurrence. Finally, the HLA * A 32:01 allele was cited as the most frequent in all proteins, and the gp21 and HBZ proteins showed similar profiles with regard to the occurrence of the most frequent HLA alleles. The HAM/TSP clinical profile showed the highest number of molecular variations among the studied proteins: there were 42 “protein alleles” against 19 of individuals with ATLL and 16 of ASS individuals (Non-HAM/TSP). The affinity findings revealed that 9 epitopes showed differences in affinity to HLA molecules, 6 of them were associated with ATLL individuals, 4 with sHAM/TSP individuals and 2 with ASS individuals. We conclude that there is no epitope presentation profile that is associated with the host clinical status, since there was great similarity in the HLA alleles and in the predicted epitopes positions among the “protein alleles”. However, we have identified important molecular variations in the epitopes prediction, especially in the genomes of individuals with ATLL and HAM/TSP. In Chapter II, we looked for markers in the host, in a group of infected individuals (HAM/TSP and asymptomatic) (N = 44). For this, we have performed the determination of Exoma through the Illumina Platform and using a chip for 551,004 SNPs. The overall genotyping rate of samples was 0.997001, with a loss of 35,163 SNPs (~ 6%), identified 515,841 variants. The ancestral determination revealed a proportionality of genetic contribution more marked for the African origin in the studied population. We observed a predominance of women in the case group, as has already been documented in the literature. The average age of infected individuals was 59 years (27-89 years), with an average proviral load of 55,253.41/106 cells. Among the SNPs identified, four of them stood out regarding the allele frequencies in the case and control groups, and they are: rs2857596_C, rs7917905_A, rs1265564_C and rs376863_A. After multivariate regression analysis, adjusted for ancestry, only the SNPs “rs1265564” (p = 7.2 * 10-4) and “rs376863” (p = 1.25 * 10-3) are associated with the outcome. The SNP rs1265564, was identified in the gene that codes for the CUX-2 protein that is associated with the repair of oxidized DNA by the action of reactive oxygen species produced in neurons. The initial four SNPs show to be in linkage disequilibrium with other SNPs, but none of those already described in the literature and cited in this work. We suggest a thorough search for the SNPs indicated in this work, as well as the association of host molecular markers with viral markers, as a way of understanding the process of infection and disease manifestation as a result of a complex and successful integration.
MEMBROS DA BANCA:
Presidente - 1854449 - ALINE CRISTINA ANDRADE MOTA MIRANDA MASCARENHAS
Interno - 2766939 - JOANA PAIXAO MONTEIRO CUNHA
Externo ao Programa - 2697145 - GISELLE CALASANS DE SOUZA COSTA
Externo à Instituição - MARIA FERNANDA DE CASTRO AMARANTE
Externo à Instituição - MARIA LUIZA SARAIVA PEREIRA