Expanding fungal pathogenesis: Cryptococcus breaks out of the opportunistic box

• Published in: Nature reviews. Microbiology Vol. 9; no. 3; pp. 193 - 203
• Main Authors: Kronstad, James W, Attarian, Rodgoun, Cadieux, Brigitte, Choi, Jaehyuk, D'Souza, Cletus A, Griffiths, Emma J, Geddes, Jennifer M. H, Hu, Guanggan, Jung, Won Hee, Kretschmer, Matthias, Saikia, Sanjay, Wang, Joyce
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2011; Nature Publishing Group
• Subjects: 631/326/193/2542; 692/699/249/1570/1901; 692/699/255/1672; Acquired immune deficiency syndrome; Adaptation; AIDS; Biomedical and Life Sciences; Care and treatment; Causes of; Central nervous system; Communicable Diseases, Emerging - microbiology; Cryptococcal infections; Cryptococcosis - microbiology; Cryptococcus - cytology; Cryptococcus - pathogenicity; Cryptococcus neoformans; Development and progression; Diseases; Epidemics; Fungi; HIV; Human immunodeficiency virus; Humans; Immunocompetence; Immunocompromised host; Infectious Diseases; Life Sciences; Mammals; Medical Microbiology; Microbiology; Morphology; Nervous system; Opportunistic Infections - microbiology; Parasitology; Pathogenesis; Pathogens; review-article; Spores, Fungal - pathogenicity; Virology; Virulence; Canada; British Columbia; British Columbia Canada; North America
• ISSN: 1740-1526; 1740-1534
• DOI: 10.1038/nrmicro2522

Key Points
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 pathogen of immunocompromised individuals. However, as discussed here, this view has been challenged by recent evidence of specialized host–pathogen interactions, and by the emergence of the related species
Cryptococcus gattii
as a primary pathogen of immunocompetent populations.
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.