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Comparative transcriptomics profile of macrophages in culture, infected with clinical isolates of Mycobacterium tuberculosis with different profiles of resistance to chemotherapeutic

Grant number: 11/21587-4
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2012
Effective date (End): May 31, 2014
Field of knowledge:Biological Sciences - Microbiology
Principal Investigator:Mario Hiroyuki Hirata
Grantee:Gabriela Guimarães Sousa Leite
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Tuberculosis (TB) is an infectious disease known for centuries and difficult to treat due to the increasing incidence of resistance and because of the arsenal of drugs available in the market is small. Many of these resistances are related to mutations in specific genes of Mycobacterium tuberculosis, preventing the action of the main anti-TB drugs. The success of the bacillus and progression is also due to the ability of M. tuberculosis to survive inside macrophages, being able to modulate specific metabolic pathways evading of the immune system. The macrophage is one of main effectors in the immune response against M. tuberculosis. Inside the environment is hostile to the bacilli at very low pH, and the high amount of hydrogen peroxide (H2O2) and nitric oxide (NO). However, some clinical isolates of M. tuberculosis are able to evade these mechanisms, either by increased expression of peroxides, such as the production of ammonia to alkalize the medium. Moreover, studies showed the participation of small non-coding RNAs (sRNA) in the mycobacterial persistence. Strains of M. tuberculosis such as Beijing, H37Rv or clinical isolates mono or multi-resistant, seem to have distinct profiles of intra-macrophage persistence, indicating different forms of bacillus-macrophage interaction. Understanding the mechanisms by which some bacilli can remain viable in a latent state within the granuloma or inside macrophages is necessary for understanding the disease, and understanding of the metabolic pathways involved in macrophage-bacillus interaction may provide useful information for selecting new therapeutic targets for drug development by pharmaceutical companies. Thus this study aims to analyze the transcriptome of macrophages infected with clinical isolates of Mycobacterium tuberculosis with different resistance profile, by high throughput sequencing. Messenger RNA will be isolated from macrophages infected with mono and multi-resistant clinical isolate (including Beijing strain) and H37Rv strain for sequencing on 5500xl SOLIDTM System. The macrophage´s transcriptome profiles will be analyzed and compared to determine the biochemical mechanisms involved in bacterial evasion and persistence of strains of M. tuberculosis. (AU)