The Role of Copper Homeostasis at the Host-Pathogen Axis: From Bacteria to Fungi

Abstract

Copper is an essential trace element participating in many vital biological processes, however it becomes a toxic agent when in excess. Thus, precise and tight regulation of copper homeostasis processes, including transport, delivery, storage, detoxification, and efflux machineries, is important, ensuring that only the amount needed to sustain basic biological functions and simultaneously prevent copper toxicity in the cell is maintained. Numerous exciting studies have revealed that copper plays an indispensable role at the microbial pathogen-host axis for entities ranging from pathogenic bacteria to deadly fungal species. Analyses of copper homeostases in bacteria and fungi extensively demonstrate that copper is utilized by the host immune system as an anti-microbial agent. The expression of copper efflux and detoxification from microbial pathogens is induced to counteract the host's copper bombardment, which in turn disrupts these machineries, resulting in the attenuation of microbial survival in host tissue. We hereby review the latest work in copper homeostases in pathogenic bacteria and fungi and focus on the maintenance of a copper balance at the pathogen-host interaction axis.

Keywords: bacterial pathogen; copper; fungal pathogen; immunity.

Figure 1

Copper homeostasis in Salmonella and Mycobacteria. The Salmonella genome encodes two copper exporter genes, and they produce two P-type ATPase copper efflux transporters, CopA and GolT. Both copper exporters pump copper from the cytosol into the periplasmic space. The expression of copA is regulated by CueR, which is a transcriptional repressor, and it is activated upon copper binding. CueR also controls the expression of cueP and cuiD. The translation of cueP is controlled by CpxR, which recruits RNA polymerase. The expression of the golTBS regulon is controlled by GolS. Similar to CueR, GolS responds to elevated copper levels. Additionally, both GolS and CueR sense other metals such as gold and silver. Mycobacteria utilize CtpV and mycobacterial copper transporter protein B (MctB) to eliminate intracellular copper, where CtpV pumps copper from the cytosol into the periplasmic space, and MctB pumps copper extracellularly. The two copper regulatory mechanisms are the CsoR and RicR systems. Similar to those seen in Salmonella, CsoR and RicR are transcriptional repressors, and dissociate from promoters of copper regulon genes when bound to copper. The copper-bound CsoR forms a homodimer. The apo form of CsoR binds to the regulatory promoter sequences.

Figure 2

Copper homeostasis in fungi. Fungal cells generally encode two high-affinity copper importers, Ctr1 and Ctr3 (Ctr4), except in Candida albicans, which possesses only the Ctr1 homolog. Atx1 and Ccs are two copper chaperones, delivering copper to Ccc2 and Sod1, respectively. Metallothioneins (MTs) are copper detoxification proteins that bind excess copper. Ctr2 is a vacuolar copper transporter, pumping copper from the vacuolar space into the cytosol compartment. Mac1 controls the copper depletion responses of Saccharomyces cerevisiae and C. albicans by activating the expression of copper transporters. Saccharomyces cerevisiae Ace1 responds to copper toxicity and induces MT expression. C. neoformans Cuf1 controls responses in both copper-rich and copper-poor environments. Cuf1 constitutively binds to the promoter sequences of CFT1 and CFO1.