Lessons from Cryptococcal Laccase: From Environmental Saprophyte to Pathogen

Abstract

Cryptococcus is an opportunistic pathogen that lives in the environment as a free-living yeast and inflicts disease in humans, primarily in immunocompromised patients such as organ-transplant recipients and people with HIV/AIDS. A key factor allowing emergence of this fungal pathogen is a copper-containing laccase enzyme that facilitates nutrient foraging as a saprophyte and offers protection against environmental dangers such as freeliving amoebae and mammalian macrophages during infection. The promiscuous substrate specificity of laccase facilitates the degradation of hard plant lignin polymers as well as the synthesis of lignin-like pigments from plant flavonoids and melanin pigments from dopamine. The enzyme also possesses an iron oxidase activity that prevents Fenton product formation in macrophages and another activity that allows synthesis of immune-modulatory prostaglandins that fool the host, shutting off an effective immune response. This review provides a brief overview of key points in laccase function and its role in virulence, as well as regulation and trafficking of the enzyme during the interconversion between saprophyte and pathogen, yielding insights into pathogenesis from this adaptable pathogen.

Masking the Pathogen: Evolutionary Strategies of Fungi and Their Bacterial Counterparts

“…Reduction of complement binding and opsonization is facilitated by capsular remodeling by proteins such as Lhc1 described above, minimizing the deposition of antibodies and complement [ 79 ]. The antiphagocytic properties of the PC are also potentiated by other cryptococcal factors such as the anti-phagocytic protein App1 which blocks complement 2 and 3 receptors (CR2 and CR3) [ 124 ] and virulence potentiated by the immune modulating cell wall and secreted laccase [ 125 ]. However, Cryptococcus is not primarily a pathogen of normal hosts; thus, recognition by Toll-like receptors [ 126 , 127 ], mannose receptors [ 41 ], β-glucan receptors [ 118 , 128 ] and complement [ 121 , 129 , 130 ] are sufficient to mediate clearance of even encapsulated strains in most immunocompetent hosts in the presence of intact T-cell and macrophage signaling.…”

It's not all about us: evolution and maintenance ofCryptococcusvirulence requires selection outside the human host

“…Melanin production by laccase functions as a defence mechanism inside the human host. Laccase enzymes have been widely identified across the phylogenetic kingdoms, are involved in reproduction (through conidiation, fruiting body production and sporulation), play a role in degradation (releasing cell nutrients for consumption), the protection of lignin‐like pigments (that can influence cell wall‐protective mechanisms) and act as production against oxidizing toxic compounds [reviewed in (Chen and Williamson, )]. Melanin production is also widely dispersed across bacteria, animal, plant and fungal kingdoms [reviewed in (Butler and Day, )], and is found in other fungal species capable of causing human disease including the dematiaceous fungi (‘darkly pigmented fungi’) [reviewed in (Wong and Revankar, )].…”