Copper homeostasis in Mycobacterium tuberculosis

Abstract

Copper (Cu) is a trace element essential for the growth and development of almost all organisms, including bacteria. However, Cu overload in most systems is toxic. Studies show Cu accumulates in macrophage phagosomes infected with bacteria, suggesting Cu provides an innate immune mechanism to combat invading pathogens. To counteract the host-supplied Cu, increasing evidence suggests that bacteria have evolved Cu resistance mechanisms to facilitate their pathogenesis. In particular, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, has evolved multiple pathways to respond to Cu. Here, we summarize what is currently known about Cu homeostasis in Mtb and discuss potential sources of Cu encountered by this and other pathogens in a mammalian host.

Fig. 1. Model of Cu-mediated control of Mtb in activated macrophages

Upon activation, Cu uptake in macrophages is increased due to the elevated levels of the Cu importer CTR1 and ATP7A. ATP7A traffics to the phagosome, potentially leading to the increased concentration of Cu in that compartment. To combat the toxicity of excess Cu, Mtb has at least three independent Cu resistance pathways as described in the text. The Cu-binding ferroxidase ceruloplasmin^, may contribute a source of Cu to control Mtb and other infections.