Abstract
Tuberculosis is once again the most fatal global infectious disease and has killed many more humans than any other pathogen. Despite the identification of Mycobacterium tuberculosis (Mtb) over 140 years ago, we have yet to control the epidemic. A central issue is the complexity of the host-pathogen interaction, with multiple underlying pathways leading to tuberculosis disease. This intricate relationship stems from the prolonged co-evolution of the pathogen with humans, resulting in diverse immunological processes leading to tuberculosis disease. Conversely, Mtb exposure may give a survival advantage through innate immune training, thereby providing selective pressure over millennia. Emerging methodologies, such as single-cell and spatial transcriptomics, offer a golden opportunity to understand the immunology unpinning this host-pathogen interaction at unprecedented resolution. However, these analyses will be fundamentally flawed if they do not consider the intricacies of human Mtb infection. Here, we propose that attempts to find single immunological mechanisms leading to tuberculosis are hindering progress, and we must embrace the complexity of multiple paths to disease to allow the systems biology era to deliver transformative solutions.