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Amoeba Predation of Cryptococcus neoformans Results in Pleiotropic Changes to Traits Associated with Virulence.

Publication ,  Journal Article
Fu, MS; Liporagi-Lopes, LC; Dos Santos, SR; Tenor, JL; Perfect, JR; Cuomo, CA; Casadevall, A
Published in: mBio
April 27, 2021

Amoeboid predators, such as amoebae, are proposed to select for survival traits in soil microbes such as Cryptococcus neoformans; these traits can also function in animal virulence by defeating phagocytic immune cells, such as macrophages. Consistent with this notion, incubation of various fungal species with amoebae enhanced their virulence, but the mechanisms involved are unknown. In this study, we exposed three strains of C. neoformans (1 clinical and 2 environmental) to predation by Acanthamoeba castellanii for prolonged times and then analyzed surviving colonies phenotypically and genetically. Surviving colonies comprised cells that expressed either pseudohyphal or yeast phenotypes, which demonstrated variable expression of traits associated with virulence, such as capsule size, urease production, and melanization. Phenotypic changes were associated with aneuploidy and DNA sequence mutations in some amoeba-passaged isolates, but not in others. Mutations in the gene encoding the oligopeptide transporter (CNAG_03013; OPT1) were observed among amoeba-passaged isolates from each of the three strains. Isolates derived from environmental strains gained the capacity for enhanced macrophage toxicity after amoeba selection and carried mutations on the CNAG_00570 gene encoding Pkr1 (AMP-dependent protein kinase regulator) but manifested reduced virulence in mice because they elicited more effective fungal-clearing immune responses. Our results indicate that C. neoformans survival under constant amoeba predation involves the generation of strains expressing pleiotropic phenotypic and genetic changes. Given the myriad potential predators in soils, the diversity observed among amoeba-selected strains suggests a bet-hedging strategy whereby variant diversity increases the likelihood that some will survive predation.IMPORTANCECryptococcus neoformans is a ubiquitous environmental fungus that is also a leading cause of fatal fungal infection in humans, especially among immunocompromised patients. A major question in the field is how an environmental yeast such as C. neoformans becomes a human pathogen when it has no need for an animal host in its life cycle. Previous studies showed that C. neoformans increases its pathogenicity after interacting with its environmental predator amoebae. Amoebae, like macrophages, are phagocytic cells that are considered an environmental training ground for pathogens to resist macrophages, but the mechanism by which C. neoformans changes its virulence through interactions with protozoa is unknown. Our study indicates that fungal survival in the face of amoeba predation is associated with the emergence of pleiotropic phenotypic and genomic changes that increase the chance of fungal survival, with this diversity suggesting a bet-hedging strategy to ensure that some forms survive.

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Published In

mBio

DOI

EISSN

2150-7511

Publication Date

April 27, 2021

Volume

12

Issue

2

Location

United States

Related Subject Headings

  • Virulence
  • Phenotype
  • Phagocytosis
  • Phagocytes
  • Moths
  • Mice, Inbred C57BL
  • Mice
  • Macrophages
  • Larva
  • Humans
 

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MLA
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Fu, M. S., Liporagi-Lopes, L. C., Dos Santos, S. R., Tenor, J. L., Perfect, J. R., Cuomo, C. A., & Casadevall, A. (2021). Amoeba Predation of Cryptococcus neoformans Results in Pleiotropic Changes to Traits Associated with Virulence. MBio, 12(2). https://doi.org/10.1128/mBio.00567-21
Fu, Man Shun, Livia C. Liporagi-Lopes, Samuel R. Dos Santos, Jennifer L. Tenor, John R. Perfect, Christina A. Cuomo, and Arturo Casadevall. “Amoeba Predation of Cryptococcus neoformans Results in Pleiotropic Changes to Traits Associated with Virulence.MBio 12, no. 2 (April 27, 2021). https://doi.org/10.1128/mBio.00567-21.
Fu MS, Liporagi-Lopes LC, Dos Santos SR, Tenor JL, Perfect JR, Cuomo CA, et al. Amoeba Predation of Cryptococcus neoformans Results in Pleiotropic Changes to Traits Associated with Virulence. mBio. 2021 Apr 27;12(2).
Fu, Man Shun, et al. “Amoeba Predation of Cryptococcus neoformans Results in Pleiotropic Changes to Traits Associated with Virulence.MBio, vol. 12, no. 2, Apr. 2021. Pubmed, doi:10.1128/mBio.00567-21.
Fu MS, Liporagi-Lopes LC, Dos Santos SR, Tenor JL, Perfect JR, Cuomo CA, Casadevall A. Amoeba Predation of Cryptococcus neoformans Results in Pleiotropic Changes to Traits Associated with Virulence. mBio. 2021 Apr 27;12(2).

Published In

mBio

DOI

EISSN

2150-7511

Publication Date

April 27, 2021

Volume

12

Issue

2

Location

United States

Related Subject Headings

  • Virulence
  • Phenotype
  • Phagocytosis
  • Phagocytes
  • Moths
  • Mice, Inbred C57BL
  • Mice
  • Macrophages
  • Larva
  • Humans