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Comparative study of the immune response of human macrophages infected with different strains of the Mycobacterium tuberculosis complex

Grant number: 19/21847-8
Support type:Scholarships in Brazil - Master
Effective date (Start): November 01, 2019
Effective date (End): October 31, 2021
Field of knowledge:Biological Sciences - Microbiology - Applied Microbiology
Principal Investigator:Ana Marcia de Sá Guimarães
Grantee:Felipe Silva
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:16/26108-0 - Systems and comparative biology of Mycobacterium tuberculosis complex: effects of genetic variability on bacterial phenotype, AP.JP

Abstract

Tuberculosis (TB) is an infectious disease caused by bacteria of the Mycobacterium tuberculosis complex (MTBC) and Mycobacterium canettii, and is the world´s leading infectious killer, according to the World Health Organization. The MTBC is composed of 12 genetically similar bacterial species that evolved clonally through single nucleotide mutations, deletions of regions up to 12 kb, insertion elements and duplication of a limited number of paralogous genes. MTBC genomes do not undergo major gene recombination events and do not perform horizontal gene transfer. In contrast, the related tuberculous M. canettii is not a member of MTBC and presents a genome subjected to horizontal gene transfer and recombinations, albeit presenting a significant homologous core genome with MTBC members. Despite this high genomic similarity, members of the MTBC differ in virulence profiles and host tropism. Among species of tuberculous mycobacteria with human health interest, the following stand out: M. tuberculosis (main causative agent of tuberculosis in humans), Mycobacterium africanum 1 (L6) e 2 (L5) and M. canettii, highly adapted to human beings, and Mycobacterium bovis and Mycobacterium caprae, the causative agents of zoonotic and animal tuberculosis able to infect a broader range of host species, including humans, with variable populational persistence. Unfortunately, the pathogenicity mechanisms of these tuberculous mycobacteria in humans, except for M. tuberculosis, are poorly understood. In addition, Mycobacterium canetii and M. africanum are restricted to human populations of East and West Africa, respectively. In its turn, M. bovis, and possibly M. caprae, the main pathogens of tuberculosis in animals (establishing reservoirs in these hosts), are rarely transmitted from human-to-humans, even in cases of pulmonary TB, and are not able to persist in this population. In view of these differences in host adaptability and virulence, molecular mechanisms for evasion of the immune response, used for persistence of the MTBC within macrophages, the main target cells of these pathogens, have not been fully explored. Therefore, the aim of this study is to comparatively evaluate the response of human macrophages infected with different MTBC strains by the quantification of cytokines, evaluation of cell death and RT-qPCR array of macrophage genes that are related to the immune system. We expect to identify distinct immune responses against the various tuberculous mycobacteria that may serve as basis for the understanding of the phenotypic variation comprising the clonal MTBC. (AU)