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  • Review Article
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Cryptococcus: from environmental saprophyte to global pathogen

Nature Reviews Microbiology volume 14, pages 106–117 (2016)Cite this article

Subjects

Key Points

  • Cryptococcosis is a widespread opportunistic fungal infection of humans and other animals.

  • Cryptococcus species that infect humans likely evolved as accidental pathogens in response to environmental selective pressure.

  • Recent genomic analyses have highlighted the evolutionary history of Cryptococcus spp. and narrowed down the geographical origin of an unusual, hypervirulent outbreak.

  • Despite being accidental pathogens, cryptococci display a remarkable ability to manipulate the human immune response to facilitate disease establishment and spread.

  • Detailed in vivo and in vitro characterization of Cryptococcus spp. has started to elucidate the details of multiple mechanisms of pathogenesis that probably have important roles in disease severity. These include changes in fungal morphology, interactions with host phagocytes and mechanisms that allow Cryptococcus spp. to disseminate from the lung to the central nervous system.

  • Renewed efforts to develop improved therapeutic approaches have highlighted potential new drugs and new uses for old drugs in the fight against cryptococcal disease.

Abstract

Cryptococcosis is a globally distributed invasive fungal infection that is caused by species within the genus Cryptococcus which presents substantial therapeutic challenges. Although natural human-to-human transmission has never been observed, recent work has identified multiple virulence mechanisms that enable cryptococci to infect, disseminate within and ultimately kill their human host. In this Review, we describe these recent discoveries that illustrate the intricacy of host–pathogen interactions and reveal new details about the host immune responses that either help to protect against disease or increase host susceptibility. In addition, we discuss how this improved understanding of both the host and the pathogen informs potential new avenues for therapeutic development.

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Figure 1: Inflammatory signalling in response to cryptococcal infection.
Figure 2: Infection establishment and dissemination within the human host.
Figure 3: Current and future therapies for cryptococcosis.

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Acknowledgements

The authors gratefully acknowledge the help of S. Kannambath in preparing Figure 3 and apologize to those colleagues in the field whose work could not be included in this Review owing to space constraints. R.C.M. is supported by funding from the European Research Council, Medical Research Council, Lister Institute and Royal Society. D.L.W. received support from the US National Institutes of Health (NIH) T32 training grant AI007313, a University of Minnesota Doctoral Dissertation Fellowship and a Dennis W. Watson Fellowship. K.N. is supported by funding from the NIH. T.B. is supported by funding from the Wellcome Trust and the Medical Research Council (UK). N.R.H.S. is supported by a Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology to the University of Aberdeen.

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Authors and Affiliations

  1. Institute of Microbiology and Infection and School of Biosciences, University of Birmingham, Birmingham, B15 2TT, UK

    Robin C. May

  2. Institute of Infection and Immunity, St Georges, University of London, London, SW17 0RE, UK

    Neil R.H. Stone & Tihana Bicanic

  3. Department of Microbiology and Center for Infectious Diseases, Microbiology, and Translational Research, University of Minnesota, 55455, Minnesota, USA

    Darin L. Wiesner & Kirsten Nielsen

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Correspondence to Robin C. May.

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FURTHER INFORMATION

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Glossary

Pacific Northwest outbreak

An unusual cluster of cryptococcal disease in otherwise healthy (rather than immunocompromised) individuals. First identified on Vancouver Island, British Columbia, in 1999 (and hence originally called the Vancouver Island outbreak), both the causative organism and cases of human and animal disease have now expanded into mainland Canada and the northwestern USA, prompting a renaming of the outbreak.

Iatrogenic

Caused by medical treatment. For instance, infections due to contaminated surgical instruments.

Zoonotic

A disease transmitted from animals to people.

Polyploid

Having multiple (that is, more than two) sets of homologous chromosomes.

Founder

The initial, small group of individuals that seeds a new population. For instance, the inoculum that starts an infection, or the first individuals to arrive on a new island habitat.

Quorum sensing

The regulation of gene expression or behaviour in response to changes in the local population size.

Paracrine

A signal that acts close to where it is produced, for instance on neighbouring cells.

Filamentation

The growth of an organism by elongation without division.

Major histocompatibility complex class II

(MHC class II). Molecules that are expressed on the surface of professional antigen-presenting cells (such as macrophages and dendritic cells) and present extracellular antigens to the immune system to coordinate an immune response.

T helper 1 response

A response by one subtype of CD4+ helper T (TH) cell that is generally provoked by intracellular pathogens. TH2 responses, by contrast, are typically involved in the elimination of parasitic worms, harmful allergic responses and dampening of TH1-mediated inflammation. In the context of cryptococcal infection, TH1 responses are widely thought to be protective, and TH2 responses to be detrimental.

Coalescence analyses

An evolutionary analysis method in which genetic drift is 'played backwards' to calculate common ancestry of individuals within a population and thereby estimate lineage branch points within an evolutionary phylogenetic tree.

Bipolar mating

A system to control sexual reproduction that relies on a single genetic locus at which individual organisms can carry one of two alleles, effectively generating a species with two sexes.

Diploid

Having two homologous sets of chromosomes, one from each parent.

Aneuploid

Having an 'unbalanced' set of chromosomes; for instance, having only a single copy of one chromosome in an otherwise diploid genome.

Melanization

The production of the dark, insoluble pigment melanin, which provides protection from high energy radiation and reactive oxygen molecules.

Blood–brain barrier

A specialized endothelial barrier that prevents the entry of cells or large molecules into the central nervous system.

Paracytosis

Transitioning between tissues by moving between, rather than through, adjacent cells.

Transcytosis

Transitioning between tissues by moving directly through cells, rather than between adjacent cells.

Hyaluronic acid

An abundant, high-molecular-weight polysaccharide that forms part of the extracellular matrix, particularly in neural tissue.

Cerebrospinal fluid

(CSF). A clear fluid produced in the brain that bathes the central nervous tissue and is slowly turned over.

Regulatory T cells

A type of T cell that functions to regulate the immune system, typically by suppressing the function of pro-inflammatory effector T cells.

Fungicidal

An antimicrobial agent that kills fungi, rather than simply preventing growth.

Fungistatic

An antimicrobial agent that prevents fungal growth, but does not kill the organism.

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May, R., Stone, N., Wiesner, D. et al. Cryptococcus: from environmental saprophyte to global pathogen. Nat Rev Microbiol 14, 106–117 (2016). https://doi.org/10.1038/nrmicro.2015.6

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