Reductive stress in microbes: implications for understanding Mycobacterium tuberculosis disease and persistence.

Mycobacterium tuberculosis (Mtb) is a remarkably successful pathogen that is capable of persisting in host tissues for decades without causing disease. Years after initial infection, the bacilli may resume growth, the outcome of which is active tuberculosis (TB). In order to establish infection, resist host defences and re-emerge, Mtb must coordinate its metabolism with the in vivo environmental conditions and nutrient availability within the primary site of infection, the lung. Maintaining metabolic homeostasis for an intracellular pathogen such as Mtb requires a carefully orchestrated series of oxidation-reduction reactions, which, if unbalanced, generate oxidative or reductive stress. The importance of oxidative stress in microbial pathogenesis has been appreciated and well studied over the past several decades. However, the role of its counterpart, reductive stress, has been largely ignored. Reductive stress is defined as an aberrant increase in reducing equivalents, the magnitude and identity of which is determined by host carbon source utilisation and influenced by the presence of host-generated gases (e.g. NO, CO, O(2) and CO(2)). This increased reductive power must be dissipated for bacterial survival. To recycle reducing equivalents, microbes have evolved unique electron 'sinks' that are distinct for their particular environmental niche. In this review, we describe the specific mechanisms that some microbes have evolved to dispel reductive stress. The intention of this review is to introduce the concept of reductive stress, in tuberculosis research in particular, in the hope of stimulating new avenues of investigation.