Editors' ChoiceInfectious Disease

Dissecting the Enigma of Mycobacterium tuberculosis Pathogenesis

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Science Translational Medicine  09 Jul 2014:
Vol. 6, Issue 244, pp. 244ec116
DOI: 10.1126/scitranslmed.3009802

The causal organism of tuberculosis (TB), Mycobacterium tuberculosis (Mtb), is a slow-growing yet very successful pathogen. One characteristic of Mtb that leads to this success is nonreplicating persistence (NRP), which is a reflection of growth arrest and a major contributor to the development of chronic TB infections and drug resistance. Mtb adapts to the changing physiology of the host, which allows it to persist in a human macrophage microenvironment otherwise not suitable for microbial colonization. Considering the complex nature of Mtb infection, molecular understanding of the host-pathogen interactions is imperative to address this global scourge.

The study by Abramovitch et al. reports that Mtb buffers its cytoplasmic pH in the acidic environment of the macrophage through a mechanism influenced by host-associated carbon sources and transcriptional remodeling. It has been shown that in rich medium, Mtb slows its growth at pHs below 6.4, arresting at pHs lower than 5.0. However, after 1-day exposure to pH 4.5, Mtb maintains an intracellular pH of 7.4, demonstrating its ability to buffer its cytoplasm in acidic environments. To achieve this buffering, Mtb relies on host-associated carbon sources such as those found at the intersection of glycolysis and the tricarboxylic acid cycle: pyruvate, acetate, oxaloacetate, and cholesterol. Indeed, addition of pyruvate resuscitates Mtb from growth arrest, further indicating that there is a pH-dependent growth checkpoint on metabolism. These growth-permissive carbon sources may feed central metabolism at the switch point known as the phosphoenolpyruvate-pyruvate oxaloacetate node or anaplerotic node, which plays an important role in promoting growth in a lower pH range. What’s more, this phenomenon may have evolved owing to Mtb pathogenesis, because it is not observed in nonpathogenic Mycobacterium smegmatis.

The current study emphasizes how Mtb integrates signals from environmental pH and available carbon sources to adapt to otherwise harsh host microenvironments. Increasing our understanding of host-pathogen interactions may facilitate a more comprehensive understanding of Mtb pathogenesis, resulting in potential new drug targets to curb Mtb virulence in the host.

J. J. Baker et al., Slow growth of Mycobacterium tuberculosis at acidic pH is regulated by phoPR and host-associated carbon sources. Mol. Microbiol., published online 26 June 2014 (10.1111/mmi.12688).[Abstract]

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