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Review
. 2011 Mar;9(3):193-203.
doi: 10.1038/nrmicro2522.

Expanding fungal pathogenesis: Cryptococcus breaks out of the opportunistic box

James W Kronstad  1 , Rodgoun Attarian, Brigitte Cadieux, Jaehyuk Choi, Cletus A D'Souza, Emma J Griffiths, Jennifer M H Geddes, Guanggan Hu, Won Hee Jung, Matthias Kretschmer, Sanjay Saikia, Joyce Wang
Affiliations
Review

Expanding fungal pathogenesis: Cryptococcus breaks out of the opportunistic box

James W Kronstad et al. Nat Rev Microbiol. 2011 Mar.

Abstract

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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Figures

Figure 1
Figure 1. Morphologically distinct cell types contribute to virulence in Cryptococcus neoformans
Spores and dessicated yeast cells initiate infection upon inhalation. Spores result from either (a) unisexual mating of MATα cells to establish a monokaryotic cell type or (b) mating and cell fusion between cells of opposite (MATa or MATα) mating type and subsequent dikaryon formation. In both cases, sexual development within the filamentous monokaryon or dikaryon results in meiosis and sporulation , , . The spores germinate to produce haploid, yeast-like cells that divide by budding. The yeast cells may become desiccated in the environment such that their small size allows inhalation deep into lung tissue. Germination of spores or vegetative growth of yeast cells in lung tissue results in the proliferation of budding cells and the formation of giant cells in a fraction of the population , , . Note that the cells are not drawn to scale. MAT, mating-type locus.
Figure 2
Figure 2. Interactions of fungal cells with phagocytic cells and dissemination through the blood brain barrier
a | Fungal cells in the lung are readily phagocytosed by alveolar macrophages and other phagocytic cells such as neutrophils. However, the subpopulation of giant cells in the lungs is refractory to phagocytosis and may remain extracellular , . In the absence of immune clearance, the fungus proliferates both intracellularly and extracellularly . b | The fungal cells may escape from the phagosomes of macrophages by an expulsion mechanism that maintains the viability of both cell types , . c | The expulsion process can also result in cell to cell movement of the fungus when expulsion results in passage of yeast cells between adjacent macrophages , . d | Fungal cells may be contained within macrophages by transient inhibition of expulsion by actin cage formation (caging) . Free fungal cells or those present in phagocytic cells enter the bloodstream and reach the central nervous system , . e | Once in the microcapillaries of the brain, evidence is accumulating that fungal cells cross the endothelium via a ‘Trojan horse’ mechanism, inside phagocytic cells . f | Observations by intravital microscopy also support an additional mechanism whereby the fungal cells cross the capillary endothelium by direct transcytosis . It has been proposed that a morphological change occurs during this process. Specifically, the spherical yeast cells adopt a more ovoid shape at the site of initial interaction with endothelial cells . g | Expulsion of yeast cells into the brain parenchymal may occur following delivery by phagocytic cells.
Figure 3
Figure 3. Giant cell formation and variation in genome copy number
The majority of yeast cells isolated from clinical and environmental sources have a haploid (1N) genome copy number, although diploid (2N) isolates can be obtained at a frequency of ~8% , , . These appear to be the result of mating interactions between strains with A and D capsular serotypes, and some of these strains are aneuploid (e.g., 2N-1) . The giant cell formation observed in infected lung tissue is accompanied by endoreplication resulting in elevated genome copy number (e.g., tetraploid (4N), octaploid (8N), etc.) without mitosis , . The small cells produced by budding from giant cells may be haploid or diploid cells. The variation in ploidy for giant cells reflects dynamic expansions and contractions of genome copy number. In addition, the observed aneuploidy (e.g., 2N-1, 1N+1) for some clinical and environmental isolates may be a result of chromosome copy number variation that occurs during transitions of cells of different ploidies ,.
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References

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