The galvanizing of Mycobacterium tuberculosis: an antimicrobial mechanism

Abstract

Evolving under constant threat from invading microbes, macrophages have acquired multiple means of killing bacteria. In this issue of Cell Host & Microbe, Botella and colleagues (Botella et al., 2011) describe a novel antimicrobial mechanism based on elevated levels of intraphagosomal Zn(2+) and the corresponding induction of bacterial genes to ameliorate this host-derived stress.

Figure 1

This diagram illustrates the sequence of events that lead to increased Zn²⁺ concentration within the Mycobacterium tuberculosis-containing phagosome, and the subsequent up-regulation of both host and bacterial genes in response to free Zn²⁺. During phagocytosis of Mtb the NADPH Oxidase complex is formed on the phagosomal membrane and generates reactive oxygen intermediates (ROIs). These ROIs signal back on the host cell and induce release of free Zn²⁺ from intracellular stores, such as the mitochondria. The free Zn²⁺ is transported into the Mtb vacuole and other endosomal compartments through unknown Zn²⁺ transporters. Within the phagosome, this increase in free Zn²⁺, which is potentially toxic to Mtb, is countered through the up-regulation of the bacterial Zn²⁺ efflux pump CtpP. Within the host cell, the increase in cytoplasmic Zn²⁺ induces the migration of metal regulatory transcriptional factor 1 (MTH1) to the nucleus where it up-regulates transcription of genes encoding metallothioneins and the Zn²⁺ efflux pump ZnT1. ZnT1 is assembled in the plasmalemma and pumps free Zn²⁺ out of the infected cell.