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• W3105656346 abstract "Abstract A remarkable aspect of the human fungal pathogen Cryptococcus neoformans is the morphological changes triggered by the interaction with the host. During infection, a specific morphological change in cell size is observed, particularly in lung tissue, from regular 5 to 7 µm cells (RCs) to titan cells (TCs, > 10 µm and up to 100 µm). However, the stable and reproducible generation of large quantity of TCs was only possible during experimental infection. We implemented here in vitro conditions allowing TCs generation with the aim to understand the ancestry of TC, the environmental determinants of TCs formation and perform easily phenotype/genotype analysis to uncover genetic factors underlying TCs formation. This paper reports robust in vitro conditions that generates yeasts cells harboring the main characteristics of TCs: large (>10 µm), uninucleate and polyploid cells harboring a single large vacuole with a dense capsule surrounding a thickened melanized cell wall. We observed that TCs formation begins as soon as 8 hours after induction, with a maximal proportion of TCs obtained after 24 hours. TCs derived for the initial oldest cells (mother cells) rather than from daughter cells. Hypoxia, nutrient starvation and low pH stresses were the main factors that trigger TCs formation, while quorum sensing factors like the initial inoculum concentration and the addition of pantothenic acid also impacted TCs formation. Antifungal drugs, resulting in inhibition of ergosterol (fluconazole), or proteins and nucleic acids (flucytosine), altered TCs formation, as did hosts-related products such as serum, phospholipids and anti-capsular antibodies in our settings. We then explored genetic factors important for TCs formation using two approaches. Using strains from H99 lineage strains among which few genetic differences have been described, we showed that TCs formation was dependent on Lmp1, Sgf29 and Gpr4/5-Rim101 proteins. Then, based on a the analysis of natural Pkr1 loss-of-function clinical isolates and serial clinical isolates, we observed the important role of Pkr1 protein, a negative regulator of the cyclic adenosine monophosphate / protein kinase A (cAMP/PKA), for TCs formation. These strains also emphasize the structural and functional relationship between Pkr1 and Pka. Our results provide new insights into TCs biogenesis with identification of multiple important factors/pathways involved. The implementation of such standardized and robust in vitro conditions pave the way for future research focusing on the genetic basis of TCs biogenesis, biology of TCs and the ontology of morphological changes in Cryptococcus neoformans. Author Summary Cryptococcus neoformans is a yeast that is capable of morphological change upon interaction with host. Particularly, in the lung of infected mice, a subpopulation of yeast evolves toward gigantism (titan cells size from 10 to 100 µm) that include other characteristics such as thickened cell wall, dense capsule, polyploidization, large vacuole with peripheral nucleus and cellular organelles. The generation of large number of such cells outside the lung of mice have been described but was not reproducible nor standardized. We here report standardized, reproducible, robust conditions of generation of titan cells and explored the environmental and genetic factors underlying the genesis of these cells. We showed that Titan cells were generated upon stresses such as change in the medium, nutrient deprivation, hypoxia and low pH. Using collection of well characterized reference strains and clinical isolates, we validated with our model the AMPc/PKA/Rim pathway as the major genetic determinant of titan cell formation. This study opens the way for a more comprehensive picture of the ontology of morphological changes in Cryptococcus neoformans." @default.
• W3105656346 created "2020-11-23" @default.
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• W3105656346 date "2017-09-20" @default.
• W3105656346 modified "2023-09-28" @default.
• W3105656346 title "Identification of environmental and genetic factors important for Cryptococcus neoformans titan cell formation using new in vitro inducing conditions" @default.
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