Live or let die: the intracellular fate of pathogenic mycobacteria

Mycobacteria are best known for the notorious pathogen that causes tuberculosis (TB): the most lethal bacterial infection, even today. Moreover, we recently see an alarming national and international increase in infections with nontuberculous mycobacteria (NTM), which are emerging as important opportunistic pathogens of humans. The urgency of therapeutic innovations is stressed by the lack of effective vaccines and the global rise in antibiotic-resistant mycobacteria. Here, we will unite leading experts in microbiology, structural biology, cell biology, genetics, and immunology, to spearhead preclinical research into the poorly understood host-pathogen interface in mycobacterial infections, and to improve the knowledge flow between the TB and NTM research fields. In this unique combination, we will address key research questions from the pathogen side, from the host side, and from a translational perspective. First, the roles of mycobacterial secretion systems and secreted virulence factors in NTM lung infections are currently unknown and different from those in TB. We aim to uncover how these elusive virulence mechanisms function to let mycobacteria establish their intracellular niche. Second, we aim to identify key host factors that control the intracellular trafficking of mycobacteria in TB and NTM infections, and that mediate the cell death pathways that mycobacteria induce to optimize their growth conditions. Third, we aim to target these host pathways by drug repurposing strategies to enhance the intracellular killing of mycobacterial pathogens. We will include clinical isolates from TB and NTM patients in these investigations to assess the therapeutic potential. This project will break new ground by: 1) Delivering mechanistic understanding of the similarities and differences in host evasion strategies of mycobacteria in TB and NTM infections, 2) Revealing the host defense processes that most effectively restrict intracellular mycobacterial growth, and 3) Providing clues to intervene with these host-pathogen interaction mechanisms to improve the clinical outcome of mycobacterial infections.