Identification of innate immune response factors on liver associated to protection against Mycobacterium tuberculosis infection

Abstract

The increasing numbers of tuberculosis infected people, the rising of Mycobacterium tuberculosis multi-drug resistant (MDR) strain and further the extensively-drug resistant strain (XDR), pursued to new challenges on scientific community regarding of prophylactic and therapeutic tools for tuberculosis (TB) control. To develop new strategies to combat TB is necessary to understand the role and relevance between the several components of the immune response. In humans, when the immune response is not sufficient to control the bacilli growth, the infection by M. tuberculosis can spread to other organs, named extrapulmonary tuberculosis. In this sense, the TB in liver is rarely documented and represents one of the latest internal organs to be infected, phenomena that has not been entirely elucidated. In agreement with results achieved in humans, previously studies from Núcleo de Pesquisa em Tuberculose (NPT) showed that the number of colony forming units counted in liver of mice infected with M. tuberculosis is around 1000 to 10000 times less than recovered from lungs or spleen. On the other hand, it is well known that the immune response on liver is very efficient against different pathogens. Thus, the aim of this work is to investigate the components related to the innate immune response in the hepatic environment that works efficiently killing the mycobacteria in this organ. In this proposal will be evaluated factors associated to macrophage activation that are resident in the liver (named Kupffer cells), compared to alveolar macrophage activation during M. tuberculosis infection in vitro and in vivo. At different time points, will be evaluated the presence of cell populations that interact with Kupffer cells, like NK, NKT and T³´ cells, as the evaluation of apoptosis or necrosis induction on alveolar macrophages and Kupffer cells. Furthermore, to contribute for global evaluation of phenotypic changes observed after infection and to correlate among the achieved results, studies using large-scale gene expression analysis and epigenetic changes will be performed on lung and liver macrophages. In this sense is expected that the identification of immune system components that contribute to liver preservation during infection will allow the description of biomarkers and/or therapeutic targets related to control the pulmonary TB.