Copper at the Fungal Pathogen-Host Axis

Abstract

Fungal infections are responsible for millions of human deaths annually. Copper, an essential but toxic trace element, plays an important role at the host-pathogen axis during infection. In this review, we describe how the host uses either Cu compartmentalization within innate immune cells or Cu sequestration in other infected host niches such as in the brain to combat fungal infections. We explore Cu toxicity mechanisms and the Cu homeostasis machinery that fungal pathogens bring into play to succeed in establishing an infection. Finally, we address recent approaches that manipulate Cu-dependent processes at the host-pathogen axis for antifungal drug development.

Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase

“…As seen in Fig. 6A, serum Cu levels progressively increased over the entire course of infection, consistent with the notion of elevated host Cu during infection and inflammation (11,13,14,17,18,(50)(51)(52). However, kidney Cu did not follow suit.…”

“…A well-accepted concept in innate immunity is host-imposed Cu toxicity, where elevated Cu serves as an effective biocide against microbial pathogens (11,13,14,17,18,(50)(51)(52). Our studies reveal two faces of host Cu during infection with C. albicans: while serum Cu elevates, Cu can become limiting at the major site of infection in the kidney.…”

“…Instead studies with Mycobacterium tuberculosis, Salmonella, Escherichia coli, and Cryptococcus neoformans have inferred the opposite, where the host elevates this metal to attack pathogens with Cu toxicity (11)(12)(13)(14)(15). Cu is an effective antimicrobial agent (16)(17)(18), and during infection host elevations in Cu can occur in macrophages (13,14) and in certain tissues (e.g., the lung during pulmonary invasion by C. neoformans) (11). However, not all tissues may exhibit a heightened Cu response as has been reported for the brain during C. neoformans invasion (19,20).…”

Bacterial copper storage proteins

“…As mentioned in the introduction, and covered in previous Minireviews in this Series, the interplay between Cu homeostasis systems in a pathogen and host is emerging as important for virulence (30)(31)(32)(33)(34)91). Compared to nutritional immunity used to withhold other essential metal ions, hosts are thought to expose invading pathogens to Cu (32,33,91).…”

“…Compared to nutritional immunity used to withhold other essential metal ions, hosts are thought to expose invading pathogens to Cu (32,33,91). In mammalian hosts ATP7A pumps Cu into the phagolysosomal compartment and Cu homeostasis systems can protect the pathogen against this attack (30)(31)(32)(33)(91)(92)(93). A number of possible defence approaches have been identified, such as Cu efflux and sequestration, including by a Cu(II)-binding siderophore (34,94).…”