Cryptococcus neoformans is generally considered to be an opportunistic pathogen because of its tendency to infect immunocompromised individuals. However, this view has been challenged by recent discoveries of specialized interactions between the fungus and its mammalian hosts, and by the emergence of the related species Cryptococcus gattii as a primary pathogen of immunocompetent populations.
Methods have been developed to separate the yeast cells (4–10 μm) from the spores (1–2 μm in diameter) that result from sexual development and meiosis in C. neoformans. The spores are infectious, as has long been suspected, and they are readily phagocytosed by macrophages in the absence of an opsonin, whereas yeast cells require prior opsonization.
C. neoformans and C. gattii disseminate from the lung and cross the blood–brain barrier (BBB) to cause meningoencephalitis. The fungal cells cross the BBB directly by transcytosis through endothelial cells lining vessels in the brain, and by a 'Trojan Horse' strategy that involves transport in phagocytic cells.
Intracellular cryptococcal cells residing in phagosomes can escape their phagocytic host cells by expulsion and by cell-to-cell transfer between macrophages. Cycles of actin polymerization (actin 'flashes') seem to form transient cages around phagosomes, potentially providing a barrier to expulsion.
C. gattii has emerged as a pathogen of immunocompetent humans and animals in western North America. The associated C. gattii strains appear to have a high intracellular proliferation rate in macrophages, and this is correlated with their virulence; they also trigger a reduced protective inflammatory response compared with the response triggered by a representative C. neoformans strain.
Giant cells (up to 100 μm) account for ∼20% of the cryptococcal burden during lung infection. These cells are polyploid and resistant to phagocytosis.
Studies with fresh isolates of C. neoformans from patients with AIDS revealed that mixed infections, as well as changes in ploidy resulting from endoreplication, are more common during cryptococcosis than previously thought. In addition, clinical isolates and strains that display antifungal-drug resistance can harbour disomic chromosomes.
Cryptococcus neoformans is generally considered to be an opportunistic fungal pathogen because of its tendency to infect immunocompromised individuals, particularly those infected with HIV. However, this view has been challenged by the recent discovery of specialized interactions between the fungus and its mammalian hosts, and by the emergence of the related species Cryptococcus gattii as a primary pathogen of immunocompetent populations. In this Review, we highlight features of cryptococcal pathogens that reveal their adaptation to the mammalian environment. These features include not only remarkably sophisticated interactions with phagocytic cells to promote intracellular survival, dissemination to the central nervous system and escape, but also surprising morphological and genomic adaptations such as the formation of polyploid giant cells in the lung.
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We gratefully acknowledge support from the National Institute of Allergy and Infectious Diseases, US National Institutes of Health (RO1 AI053721) and the Canadian Institutes of Health Research. J.W.K. is a Burroughs Wellcome Fund Scholar in molecular pathogenic mycology.
The authors declare no competing financial interests.
A combination of infection and inflammation of the meninges (membranes surrounding the central nervous system) and the brain.
A polysaccharide layer that surrounds cryptococcal cells and is composed of glucuronoxylomannan and galactoxylomannan.
A brown or black polymer that is deposited in the fungal cell wall and results in part from the catalytic activity of the enzyme laccase on substrates such as L-3,4-dihydroxyphenylalanine (L-DOPA), the dopamine precursor.
Pertaining to a cell: containing more sets of chromosomes than a cell in the typical haploid (one set) or diploid (two sets) condition.
The binding of an antibody or other protein to the surface of a pathogen cell to target that cell for phagocytosis.
- Dectin 1
(Also known as CLEC7A.) A receptor protein on the surface of immune effector cells that recognizes β-glucans on fungal cell walls to trigger an antifungal defence response.
A member of the integrin adhesion receptor family that is expressed on leukocytes. CR3 is composed of a heterodimer of CD11b (also known as αM integrin or ITGAM) and CD18 (also known as ITGB2), and recognizes fungal mannose and β-glucans.
- Blood–brain barrier
A barrier that restricts the passage of solutes and microbes from the capillaries of the central nervous system into the brain. This barrier is created by capillary endothelial cells that are connected by tight junctions.
- Intravital microscopy
A technique for the direct microscopic observation of cellular interactions in the tissue of an anaesthetized animal. When coupled with spinning-disk confocal microscopy, the method allows images of optical sections of cells to be collected in narrow focal planes.
A differentiated cell type that functions as an infection structure to mechanically penetrate the host surface; typically used by fungal pathogens to penetrate plant cell walls.
- Arp2/3 complex
A heptameric protein complex that is a major component of the actin cytoskeleton; the actin-related proteins Arp2 and Arp3 function in the nucleation of new actin filaments.
- WASP protein
A member of a family of proteins, named after Wiskott-Aldrich syndrome (which results from mutations in the WAS gene), that bind to and activate the Arp2/3 proteins for subsequent nucleation of actin filaments.
- Intracellular proliferation rate
A measure of the relative intracellular parasitism, calculated by dividing the maximum intracellular number of fungal cells in phagocytes by the number of cells at the start of an experiment.
A classification of cryptococcal isolates based on antibody recognition of the fungal polysaccharide capsule; Cryptococcus neoformans can be serotype A, D or AD, and Cryptococcus gattii can be serotype B or C.
DNA replication without subsequent mitosis, resulting in clear doubling events for the genome.
The possession of an unusual complement of chromosomes, such as disomy arising from having two copies of a particular chromosome in a cell.
A reversible, adaptive resistance to an antimicrobial drug such that a subpopulation of cells displays the ability to grow in the presence of the drug.
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Kronstad, J., Attarian, R., Cadieux, B. et al. Expanding fungal pathogenesis: Cryptococcus breaks out of the opportunistic box. Nat Rev Microbiol 9, 193–203 (2011). https://doi.org/10.1038/nrmicro2522
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