Full text
| |
| Author(s): |
Felipe Teixeira Lima
Total Authors: 1
|
| Document type: | Doctoral Thesis |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2021-09-20 |
| Examining board members: |
Fabiani Gai Frantz;
Larissa Dias da Cunha;
María Eugenia Guazzaroni;
Luana Silva Soares
|
| Advisor: | Fabiani Gai Frantz |
| Abstract | |
The development of alternatives to curb tuberculosis (TB), combined with the need for a broad understanding of the mechanisms of action of the immune response to the infection promotes the investigation of new intracellular pathways, which could be associated with potential prognostic biomarkers of the disease. Studies show that infection in experimental mice with Mtb (Mtb), among the possible organs affected, the liver presents an efficient response against infection when compared to the lung and spleen. Our hypothesis is that in the liver, some effector mechanism of the immune response is effective in eliminating the bacillus and consequently controls the disease, while it could not be activated in organs where the bacillus subverts the effector response. Our aim was to analyze in silico data already obtained from the transcriptome in search of genes and epigenetic enzymes differentially expressed in total liver and lung cells of mice experimentally infected with Mtb, which were associated with the regulation of the immune response in both organs, in order to allow the spread of the bacillus in the lung, while promoting its control in the liver. In the in silico analysis, 7 genes, Creb3l1, Trim17, Myo7b, Cyyr1, Cbs, Krt23 and Cyp3a43 were identified as differentially expressed and related to control or susceptibility. The next aim was to validate the identified targets were validated in vitro by infecting human monocytes with Mtb, to identify potential biomarkers. Through the knockdown of selected mRNA by RNA interference, we observed that the transcriptional profile could be reversed, which induced inhibition of the effector functions of monocytes. We demonstrate that the the expression of Creb3l1, Trim17, Cyyr1, Myo7b and Hdac9 and repression of Cbs, Krt23 and Cyp3A43, induces the production of cytokines such as IFN-?, IL-2 and CCL5/Rantes, and as a consequence the induction of apoptosis and resistance to infection. However, when there is a reduction in the expression of genes Creb3l1, Trim17, Cyyr1, Myo7b with a concomitant increase in the expression of Cbs, Krt23 and Cyp3A43, there is greater production of IL-4 and cell death by necrosis, which results in the persistence of mycobacteria and consequent profile of susceptibility profile. The expression of these genes are under epigenetic control and can be modulated in vitro through treatment with epidrugs. Thus, we conclude that the set of genes identified here can integrate a biosignature to predict the course of infection in tuberculosis, and the differential modulation of these 7 genes can favor can favor a scenario of resistance or susceptibility in human tuberculosis. (AU) | |
| FAPESP's process: | 18/14968-0 - Prospecting the transcriptome of cells from mice infected with Mycobacterium tuberculosis for the validation of epigenetic markers related to protection in Tuberculosis |
| Grantee: | Felipe Teixeira Lima |
| Support Opportunities: | Scholarships in Brazil - Doctorate |