Copper as a fungal virulence determinant

 http://www.nature.com/nchembio/journal/v4/n3/full/nchembio.72.html

t has long been established that invading pathogens must compete favorably for limited nutrients to both establish and maintain a successful host infection. Although iron has been well characterized as a virulence determinant in bacterial and fungal infections, recent studies indicate that Cu modulates critical virulence determinants, with its role extending beyond functioning solely in iron acquisition. Cryptococcus neoformans is an opportunistic human fungal pathogen that causes life-threatening infections in individuals and also represents the major causative agent of fungal meningitis. Infection, which is initiated in the lung, elicits an immediate host innate immune response in which activated alveolar macrophages phagocytose the fungal cells and initiate a cascade of events that culminates in the release of microbiocidal levels of ROS, an event known as the oxidative burst. Although C. neoformans can evade this host response through polysaccharide capsule production, it is thought that this microorganism uses macrophage residency as an efficient mechanism to evade further host immune attack and possibly enable systemic bloodstream infection and dissemination.Among the many transcriptional changes that accompany adaptation to the macrophage intracellular milieu, expression of the two laccase-encoding genes and the Cu-dependent iron ferroxidase/permease system is upregulated. Laccase is a multi-Cu enzyme that oxidizes phenolic compounds and is involved in melanin biosynthesis. Melanin, a bona fide virulence factor, is thought to bind superoxide and is critical to intracellular adaptation because it provides protection against ROS generated during the oxidative burst. In view of this, it would be expected that acquisition of adequate Cu levels would contribute toward virulence, and more so in the nutrient-limited environment of the host. Genetic analysis in C. neoformans has demonstrated that the Ctr4 high-affinity Cu¹⁺ transporter, which is functionally analogous to Ctr1 in baker’s yeast, and its corresponding transcriptional regulator Cuf1 (Mac1), are required for the infection of the brain but not the lung in mouse models of cryptococcosis