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Prospecting the transcriptome of cells from mice infected with Mycobacterium tuberculosis for the validation of epigenetic markers related to protection in Tuberculosis

Grant number: 18/14968-0
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): November 01, 2018
Effective date (End): August 31, 2020
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Fabiani Gai Frantz
Grantee:Felipe Teixeira Lima
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Tuberculosis (TB) is one of the leading causes of death from bacterial infection in the world today. Thus, the development of alternatives for TB control is necessary, and the understanding of mechanisms of action of the immune response to infection, in several situations, is the basis for a possible solution. In experimental infection in susceptible mice, and in the extrapulmonary clinical presentation of TB, the bacillus spreads to other organs besides the lung. Among the possible affected organs, the liver appears to present a very efficient response against the infection when compared to the lung and spleen, presenting numbers of colony forming units 1,000 to 10,000 times lower in relation to the lung. The liver contains innumerable cells of the immune system that specialize in the detection, capture and defense against circulating pathogens and distinguish them from tolerogenic antigens, such as those from food. In view of this, our hypothesis is that in the liver, certain signaling pathways or effector mechanisms are quite efficient for the control of infections and could not be activated in the organs where the bacillus escapes from the immune system. Thus, the macrophage transcriptome of the liver and lung was carried out in previous work of our research group, with the objective of identifying factors that differentiate the immune response in both organs, in order to allow the spread of the bacillus in the lung, while promote their control in the liver. Mechanisms of epigenetic control may be related to post-transcriptional changes that favor the growth of the bacillus in the susceptible host or, on the other hand, favor the control of the disease in the resistant individuals. Therefore, with this work, our objective is to analyze in silico the data already obtained from the transcriptome, in search of genes that encode epigenetic enzymes differentially expressed in the liver and lung. These enzymes can insert or remove chemical clusters of DNA or histones and allow proteins to be produced or not. Thus, once detected which enzymes are associated with protection or in silico susceptibility, the targets will be validated in vitro. Cells from the peripheral blood of healthy donors will be infected in vitro with M. tuberculosis and will be treated with inhibitors of the enzymes. After inhibition of these enzymes, the immune response and bacterial growth will be evaluated. This will allow us to identify epigenetic biomarkers involved in the TB response in human cells in order to suggest specific targets for therapeutic purposes. (AU)