Copper in infectious disease: Using both sides of the penny

The transition metal Cu is an essential micronutrient that serves as a co-factor for numerous enzymes involved in redox and oxygen chemistry. However, Cu is also a potentially toxic metal, especially to unicellular microbes that are in direct contact with their environment. Since 400 BCE, Cu toxicity has been leveraged for its antimicrobial properties and even today, Cu based materials are being explored as effective antimicrobials against human pathogens spanning bacteria, fungi, and viruses, including the SARS-CoV-2 agent of the 2019-2020 pandemic. Given that Cu has the double-edged property of being both highly toxic and an essential micronutrient, it plays an active and complicated role at the host-pathogen interface. Humans have evolved methods of incorporating Cu into innate and adaptive immune processes and both sides of the penny (Cu toxicity and Cu as a nutrient) are employed. Here we review the evolution of Cu in biology and its multi-faceted roles in infectious disease, from the viewpoints of the microbial pathogens as well as the animal hosts they infect.