Acid Resistance inMycobacterium tuberculosis

Responses to acid have been studied extensively in enteric pathogens, such as Escherichia coli, Vibrio cholerae, and Heli- cobacter pylori that encounter the extremely low pH (pH 2 to 3) of the stomach during ingestion. In contrast, much less is known about how obligate or facultative intracellular bacterial pathogens like Mycobacterium tuberculosis respond, resist, and persist in the moderately acid environment of the phagosome or phagolysosome. The pH of the macrophage compartment, in which M. tuberculosis resides, ranges from pH 6.2 to 4.5, depending on the activation state of the macrophage (55, 81, 99). Phagosomal acidity may provide a critical cue for adapta- tion of M. tuberculosis to the host niche. At the same time, to ensure survival for what can be decades, the bacterium must prevent excessive entry of protons into its cytosol and expel them when their concentrations threaten the pH homeostasis that most organisms maintain. Here we review current under- standing of the ability of M. tuberculosis to adapt to phagoso- mal levels of acid. It has been challenging to dissect the role of phagosome acidification in the pathogenesis of tuberculosis, because it is accompanied by and synergizes with other host defenses. Similarly, M. tuberculosis acid resistance mechanisms appear to be cross-protective against other forms of stress, making it difficult to directly relate a defect in acid resistance to impaired virulence. Notwithstanding, the phenomenon is central to the pathogenesis of tuberculosis and thus might offer points of vulnerability that could be exploited by new chemo- therapeutics.