Interference of mycobacterium tuberculosis with the endocytic/ antigen presentation pathways on macrophages and dendritic cells

Tese de doutoramento, Farmácia (Biologia Celular e Molecular), Universidade de Lisboa, Faculdade de Farmácia, 2014

Tuberculosis is a worldwide health concern, caused by the bacterium Mycobacterium tuberculosis (MTB) that causes the death of approximately 1.3 million people per year making it the deadliest bacterial infection for human beings. Although antibiotic treatment exists, its severity and long duration hampers the implementation and compliance, leading to the generation of multiresistant strains. This thesis proposes that by enhancing the cellular immunity against the bacteria we can improve the therapeutic and reduce the emergence of resistant strains. In order to test this hypothesis, we first explored the regulation of lysosomal cathepsins caused by MTB to identify key molecules being subverted by the pathogen. Cathepsins are major proteolytic enzymes active in the endocytic pathways and thus, are interesting targets to study in the context of an intracellular pathogen such as MTB. Then, it is revealed that MTB regulates one of these cathepsins, cathepsin S, by manipulating the expression of the micro-RNA, miR-106b-5p. This identified one potential target to counter MTB-mediated manipulation of the host cells. Furthermore, it is shown that pharmacologic drugs already approved for other pathologies can be used to alter the phagosomal environment and improve macrophage-mediated killing of MTB. Finally it is shown that restriction of outer-membrane transport is a resistance factor of MTB and a novel outer-membrane channel is an entry pathway for drugs and host microbicidal molecules that may be exploited in the future. Altogether, we show that we can improve host cell-mediated antimycobacterial mechanisms and we propose several molecules that may be targeted for this purpose.

Fundação para a Ciência e a Tecnologia (FCT)