Grant: Project Grant

Most fundamental research on tuberculosis (TB) uses the bacteria Mycobacterium tuberculosis, the agent responsible for the majority of human TB. Just as SARS and SARS-Co-V2 came from bat coronaviruses, M. tuberculosis comes from a larger pool of pathogens, called the M. tuberculosis complex (MTBC). MTBC members cause TB in a wide variety of hosts. The MTBC are a valuable group of bacteria to study because 1) they spread across a broader range of hosts than M. tuberculosis, and 2) they cause a more aggressive disease following experimental infection. As such, they can teach us about the evolution of the human pathogen and reveal virulence mechanisms that may not be observed with M. tuberculosis-based studies. This proposal studies the classic human pathogen (M. tuberculosis) and two cattle-associated pathogens, M. bovis and M. orygis. M. bovis is the classically described cause of TB in the Western world; it is a health and economic problem for livestock, and a health threat for humans. M. orygis is increasingly recognized as the counterpart of M. bovis in South Asia, causing livestock TB and disseminated infections in humans. Because our unpublished investigations reveal marked differences in virulence between M. tuberculosis (chronic disease) and M. bovis and M. orygis (acute, severe disease), we aim to unravel the reasons for these differences in a set of laboratory-based studies. The study of infections with different MTBC informs on fundamental mechanisms of disease and provides translational value to evaluate novel vaccines and treatments. These organisms already cause spillover infections in humans now, therefore they pose a threat for TB control and elimination if we focus our attention only on M. tuberculosis. Understanding a broader range of MTBC organisms is expected to provide a broader pool of resources to address all forms of TB.