The Cryptococcus neoformans Titan cell is an inducible and regulated morphotype underlying pathogenesis

Ivy M Dambuza, Thomas Drake, Ambre Chapuis, Xin Zhou, Joao Correia, Leanne Taylor-Smith, Nathalie Legrave, Tim Rasmussen, Matthew C. Fisher, Tihana Bicanic, Thomas S Harrison, Marcel Jaspars, Robin C May, Gordon D Brown, Raif Yuecel, Donna M MacCallum, Elizabeth Ballou* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

90 Citations (Scopus)
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Fungal cells change shape in response to environmental stimuli, and these morphogenic transitions drive pathogenesis and niche adaptation. For example, dimorphic fungi switch between yeast and hyphae in response to changing temperature. The basidiomycete Cryptococcus neoformans undergoes an unusual morphogenetic transition in the host lung from haploid yeast to large, highly polyploid cells termed Titan cells. Titan cells influence fungal interaction with host cells, including through increased drug resistance, altered cell size, and altered Pathogen Associated Molecular Pattern exposure. Despite the important role these cells play in pathogenesis, understanding the environmental stimuli that drive the morphological transition, and the molecular mechanisms underlying their unique biology, has been hampered by the lack of a reproducible in vitro induction system. Here we demonstrate reproducible in vitro Titan cell induction in response to environmental stimuli consistent with the host lung. In vitro Titan cells exhibit all the properties of in vivo generated Titan cells, the current gold standard, including altered capsule, cell wall, size, high mother cell ploidy, and aneuploid progeny. We identify the bacterial peptidoglycan subunit Muramyl Dipeptide as a serum compound associated with shift in cell size and ploidy, and demonstrate the capacity of bronchial lavage fluid and bacterial co-culture to induce Titanisation. Additionally, we demonstrate the capacity of our assay to identify established (cAMP/PKA) and previously undescribed (USV101) regulators of Titanisation in vitro. Finally, we investigate the Titanisation capacity of clinical isolates and their impact on disease outcome. Together, these findings provide new insight into the environmental stimuli and molecular mechanisms underlying the yeast-to-Titan transition and establish an essential in vitro model for the future characterization of this important morphotype.
Original languageEnglish
Article numbere1006978
Number of pages28
JournalPLoS Pathogens
Issue number5
Publication statusPublished - 18 May 2018

Bibliographical note

We thank Prof Joseph Heitman and Prof Kirsten Nielsen for helpful discussions. We thank Dr Lukasz Kozubowski for feedback on the manuscript. We thank Prof Arturo Casadevall for the anti-capsule antibody 18B7. We are grateful to Drs Attila Bebes and Linda Duncan in the Iain Fraser Cytometry Centre (Aberdeen University), Delyth Reed, and Debbie Wilkinson, Lucinda Wight and Kevin MacKenzie in the Microscopy and Histology Core Facility (Aberdeen University) for their expert help with the cytometry and microscopy experiments. We are also grateful for the assistance of staff at the University of Aberdeen Medical Research Facility.

Funding: ERB: This work was supported by the UK Biotechnology and Biological Research Council (; BB/M014525/1). IMD: Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (; 097377). AC, DMM: UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (; NC/N002482/1). GDB: Wellcome Trust (; 102705). IMD, TD, AC, GDB, RY, and DMM: MRC Centre for Medical Mycology at the University of Aberdeen (;; MR/N006364/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


  • Cryptococcus neoformans
  • Titan cell
  • Pathogenesis


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