The Cryptococcus neoformans titanide is a pathogenic cell type that arises from typical yeast cells in response to host conditions
- 1MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom.
- 2Department of Metabolism and System Science, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom.
Abstract
Fungal morphogenesis is a major driver of disease outcome. For the opportunistic fungal pathogen Cryptococcus neoformans, extreme morphological heterogeneity within the lung environment drives dissemination, immune evasion, and drug resistance. One such cell type is the small, oval, titanide (2–4 µm). This poorly understood cell type is prevalent in lung histology as well as host-relevant in vitro conditions. In conditions that generate cellular heterogeneity, titanides comprise 4%–10% of cells 24 hours post-induction and by 72 hours are the dominant cell type. Despite their prevalence and the significance of cryptococcal morphogenesis for virulence, key questions pertaining to their origin, fate, and underlying biology remain unstudied. Using TEM, SEM, and fluorescence microscopy we demonstrate that titanides display distinct morphological features; they possess thin cell walls, single birth scars, and capsules, with reduced Pathogen-Associated Molecular Pattern exposure and altered distribution. These features distinguish titanides from previously described C. neoformans ‘small cells’ such as in vivo seed cells (6 µm, high cell-wall mannan content) and micro cells (round, <1 μm, with thick cell walls) among others. Using microfluidics, we reveal that titanides arise from yeast-like ‘typical’ mothers, highlighting the morphological plasticity of typical cells in host-relevant conditions. Upon birth, titanides have compact nuclei and do not immediately proliferate, but transfer to fresh media results in rapid swelling and cell division. Consistent with this, titanides are more resistant to some cell wall/membrane stressors and are an effective infectious propagule in a murine model. Together, these findings establish a definition and essential characterisation of the titanide cell type and provide new insight into a key player in C. neoformans cell biology and pathogenesis.
Cryptococcus neoformans cells can adopt many different phenotypes during infection. This study uses microfluidics to show that one such form, titanides, arise from typical yeast cells and form a distinct, stress-resistant infectious cell type important for adaptation and disease.
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BibTeX
@article{potton2026cryptococcus,
title = {{The Cryptococcus neoformans titanide is a pathogenic cell type that arises from typical yeast cells in response to host conditions}},
author = {Abigail M Potton and Iana Kalinina and Gordon D Brown and Maria Makarova and Sandra Catania and Dora E Corzo-Leon and Elizabeth R Ballou},
journal = {PLOS Biology},
year = {2026},
month = oct,
doi = {10.1371/journal.pbio.3004031},
url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004031},
note = {CC BY},
}
RIS
TY - JOUR
TI - The Cryptococcus neoformans titanide is a pathogenic cell type that arises from typical yeast cells in response to host conditions
AU - Abigail M Potton
AU - Iana Kalinina
AU - Gordon D Brown
AU - Maria Makarova
AU - Sandra Catania
AU - Dora E Corzo-Leon
AU - Elizabeth R Ballou
PY - 2026
DA - 2026/10/12
JO - PLOS Biology
DO - 10.1371/journal.pbio.3004031
UR - https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004031
AB - Fungal morphogenesis is a major driver of disease outcome. For the opportunistic fungal pathogen Cryptococcus neoformans, extreme morphological heterogeneity within the lung environment drives dissemination, immune evasion, and drug resistance. One such cell type is the small, oval, titanide (2–4 µm). This poorly understood cell type is prevalent in lung histology as well as host-relevant in vitro conditions. In conditions that generate cellular heterogeneity, titanides comprise 4%–10% of cells 24 hours post-induction and by 72 hours are the dominant cell type. Despite their prevalence and the significance of cryptococcal morphogenesis for virulence, key questions pertaining to their origin, fate, and underlying biology remain unstudied. Using TEM, SEM, and fluorescence microscopy we demonstrate that titanides display distinct morphological features; they possess thin cell walls, single birth scars, and capsules, with reduced Pathogen-Associated Molecular Pattern exposure and altered distribution. These features distinguish titanides from previously described C. neoformans ‘small cells’ such as in vivo seed cells (6 µm, high cell-wall mannan content) and micro cells (round, <1 μm, with thick cell walls) among others. Using microfluidics, we reveal that titanides arise from yeast-like ‘typical’ mothers, highlighting the morphological plasticity of typical cells in host-relevant conditions. Upon birth, titanides have compact nuclei and do not immediately proliferate, but transfer to fresh media results in rapid swelling and cell division. Consistent with this, titanides are more resistant to some cell wall/membrane stressors and are an effective infectious propagule in a murine model. Together, these findings establish a definition and essential characterisation of the titanide cell type and provide new insight into a key player in C. neoformans cell biology and pathogenesis. Cryptococcus neoformans cells can adopt many different phenotypes during infection. This study uses microfluidics to show that one such form, titanides, arise from typical yeast cells and form a distinct, stress-resistant infectious cell type important for adaptation and disease.
SN - 1545-7885
SN - 1544-9173
ER -