Abstract
Since the release of the first Mycobacterium tuberculosis genome in 1998, major advances have been made in understanding the biology of this pathogen, the leading infectious cause of death in modern human history. In this Review, we outline the physiological and metabolic features thought to underpin the survival, evasion and subversion strategies employed by M. tuberculosis as it drives a cycle of transmission, infection and disease in its obligate human host. We also consider adaptations to key host innate immune effectors, including the roles of granulocytes, phagosomal damage and repair, autophagy and cell death in determining host-mycobacterium outcomes. Given the increasing awareness of the importance of asymptomatic M. tuberculosis infection and transmission, we advocate for the need to ensure greater intersection between laboratory and clinical research, taking into account the environmental context in which natural infection and disease occur. We identify knowledge gaps in the field and reflect on the opportunities and challenges for integrating host, bacterium and environment into future investigations to inform intervention strategies to control tuberculosis disease.