The Sculpting of the Mycobacterium tuberculosis Genome by Host Cell–Derived Pressures

Abstract

Mycobacterium tuberculosis is an incredibly successful pathogen with an extraordinary penetrance of its target host population. The ability to infect many yet cause disease in few is undoubtedly central to this success. This ability relies on sensing and responding to the changing environments encountered during the course of disease in the human host. This article discusses these environmental cues and stresses and explores how the genome of M. tuberculosis has evolved under the purifying selections that they exert. In analyzing the response of M. tuberculosis to a broad range of intracellular pressures, it is clear that, despite genome downsizing, M. tuberculosis has retained an extraordinary flexibility in central carbon metabolism. We believe that it is this metabolic plasticity, more than any of the virulence factors, that is the foundation for M. tuberculosis ’s qualities of endurance.