The Spectrum of Interactions between Cryptococcus neoformans and Bacteria

Abstract

Cryptococcus neoformans is a major fungal pathogen that infects immunocompromised people and causes life-threatening meningoencephalitis. C. neoformans does not occur in isolation either in the environment or in the human host, but is surrounded by other microorganisms. Bacteria are ubiquitously distributed in nature, including soil, and make up the dominant part of the human microbiota. Pioneering studies in the 1950s demonstrated antifungal activity of environmental bacteria against C. neoformans. However, the mechanisms and implications of these interactions remain largely unknown. Recently, interest in polymicrobial interaction studies has been reignited by the development of improved sequencing methodologies, and by the realization that such interactions may have a huge impact on ecology and human health. In this review, we summarize our current understanding of the interaction of bacteria with C. neoformans.

Keywords: Cryptococcus; antifungal activity; bacteria; fungal pathogen; interkingdom-interactions.

Figure 1

Types of fungal–bacterial interactions. (a) Possible types of interactions between fungi and bacteria, and their respective outcomes. (b) Examples of positive and negative interaction outcomes for C. neoformans cells following exposure to bacteria. Bacteria may induce fungal proliferation, or kill fungal cells. Bacteria may also trigger the expression of fungal virulence factors (e.g., formation of melanin pigment or polysaccharide capsule), or repress formation of these factors. The different outcomes are color-coded depending on their impact on the fungus, i.e., outcomes likely to be beneficial to the fungus are boxed in blue, while outcomes likely to be unfavorable are boxed in orange.

Figure 2

The spectrum of interactions between C. neoformans and bacteria. (a) A mixture of bacteria isolated from the gastrointestinal tract of healthy pigeons kills C. neoformans. (b) Acinetobacter baumanii and C. neoformans reciprocally inhibit each other’s growth. Staphylococcus aureus kills C. neoformans by an unknown mechanism, and P. aeruginosa kills cryptococcal cells via production of pyocyanin and other factors. (c) A. baumanii induces C. neoformans capsule formation, and S. aureus preferentially attaches to and kills encapsulated C. neoformans cells. Bacillus safensis inhibits capsule formation via production of chitinase and other factors. (d) K. aerogenes produces dopamine, and diverse bacteria produce homogentisic acid (HGA), both of which serve as substrates for cryptococcal melanin biosynthesis. B. safensis inhibits fungal melanin production via chitinase activity and other factors. (e) Cell wall peptidoglycan from E. coli and Streptococcus pneumoniae induce C. neoformans titan cell formation. The murine microbiota induces fungal titanization by an unknown mechanism. The orange colored arrow-headed and blunt-ended lines indicate inducing and repressive processes, respectively, that have a negative impact on cryptococcal viability or virulence factor production. The blue colored arrow-headed lines indicate processes that have a positive influence on the formation of C. neoformans virulence factors.

Figure 3

Close-contact interactions of B. safensis with diverse fungal pathogens. (a) Schematic representation of some fungal-bacterial interactions. (I) Bacteria may secrete certain factors that enter the fungal cell; (II) bacteria may attach to the fungal cell surface and inject factors into the fungus; (III) bacteria may attach to the fungal cell and express cell-surface associated factors; and (IV) bacteria may attach to the fungal cell surface and form cell aggregates and biofilms. Additional mechanisms may exist. (b) Differential interference contrast (DIC) microscopy image of C. neoformans cells grown with B. safensis in yeast peptone dextrose medium for 24 h. Note that B. safensis appears to form a cluster of cells (indicated by a white arrow) on one side of the C. neoformans cell. (c) DIC microscopy image of C. albicans cells grown with B. safensis under fungal hypha-inducing conditions for 4 h. A bacterial cell (black arrow) can be seen attached to the fungal filament. (d) DIC microscopy image of U. maydis cells grown with B. safensis in potato dextrose broth for 24 h. A bacterial cell (black arrow) has attached to the fungal cell. Scale bars, 2 µm.