Real-Time Measurement of Host Bioenergetics During Mycobacterium Tuberculosis Infection.

摘要

The unique ability of Mycobacterium tuberculosis (Mtb) to persist in humans in a dormant, drug-resistant state, sometimes reactivating to cause tuberculosis (TB) decades after the primary infection, has puzzled scientists for years. This, together with the fact that more than one third of the world's population is latently infected with Mtb and the emergence of multi-drug resistant (MDR), extensively drug-resistant (XDR) and super XDR (S-XDR) Mtb strains constitutes a major challenge to global health. Surprisingly, very little is known about the precise mechanisms that Mtb uses to subvert host immune responses and there is an urgent need to apply new state-of-the-art tools to determine precisely how Mtb overcomes host defenses in order to establish a persistent infection. For this purpose, we will apply a novel technology that, to the best of our knowledge, has not yet been used to examine any microbial species. The application of this tool, for the first time, will reveal a wealth of previously unknown, quantitative information about the bacterial oxygen consumption rate (OCR), the extracellular acidification rate (ECAR) and reserve respiratory capacity (RRC). To date, critical information regarding Mtb bioenergetics is not available and represents a significant gap in our understanding of Mtb physiology. Secondly, real-time metabolic profiling of human macrophages infected with Mtb mutants will identify key bacterial factors that target specific components of the host ETC. Lastly, mycobacterial genes and pathways that modulate the bacterial and host bioenergetic state will be identified. These findings are expected to have an important positive impact on our understanding of mycobacterial physiology, which will result in the development of innovative approaches toward the containment and treatment of TB.