Diversity of Mycobacterium tuberculosis across evolutionary scales
Mary B O’Neill, Tatum D Mortimer, Caitlin S Pepperell
Tuberculosis (TB) is a global public health emergency. Increasingly drug resistant strains of Mycobacterium tuberculosis (M.tb) continue to emerge and spread, highlighting the adaptability of this pathogen. Most studies of M.tb evolution have relied on ‘between-host’ samples, in which each person with TB is represented by a single M.tb isolate. However, individuals with TB commonly harbor populations of M.tb numbering in the billions. Here, we use analyses of M.tb diversity found within and between hosts to gain insight into the adaptation of this pathogen. We find that the amount of M.tb genetic diversity harbored by individuals with TB is similar to that of global between-host surveys of TB patients. This suggests that M.tb genetic diversity is generated within hosts and then lost as the infection is transmitted. In examining genomic data from M.tb samples within and between hosts with TB, we find that genes involved in the regulation, synthesis, and transportation of immunomodulatory cell envelope lipids appear repeatedly in the extremes of various statistical measures of diversity. Polyketide synthase and Mycobacterial membrane protein Large (mmpL) genes are particularly notable in this regard. In addition, we observe identical mutations emerging across samples from different TB patients. Taken together, our observations suggest that M.tb cell envelope lipids are targets of selection within hosts. These lipids are specific to pathogenic mycobacteria and, in some cases, human-pathogenic mycobacteria. We speculate that rapid adaptation of cell envelope lipids is facilitated by functional redundancy, flexibility in their metabolism, and their roles mediating interactions with the host.