Copper at the Front Line of the Host-Pathogen Battle

Copper (Cu) is a transition metal used by life from bacteria to eukaryotes in many cellular processes as a biochemical cofactor and a signaling molecule. However, while Cu plays critical cellular roles, it can be toxic when allowed to accumulate to levels well beyond cellular needs. This razor's edge between the essentiality and toxicity of Cu is emerging as a critical host defense mechanism at the heart of the host-pathogen axis. Accumulating evidence suggests that the innate immune response commandeers the toxic properties of Cu to attack invading infectious organisms, while pathogenic bacteria and fungi have implemented robust mechanisms for Cu resistance. The fact that Cu resistance mechanisms are frequently found among pathogens, and required for virulence, suggests that this is an important aspect of survival in the host. Here, we suggest answers to four fundamental questions about our current understanding of the role of Cu in microbial pathogenesis.