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

Research output: Contribution to journalArticle

Authors

  • Ivy Dambuza
  • Thomas Drake
  • Ambre Chapuis
  • Xin Zhou
  • Nathalie LeGrave
  • Tim Rasmussen
  • Matthew Fisher
  • Tihana Bicanic
  • Thomas Harrison
  • Marcel Jaspars
  • Gordon Brown
  • Raif Yuecel
  • Donna MacCallum
  • Elizabeth R Ballou

Colleges, School and Institutes

External organisations

  • University of Aberdeen
  • The Francis Crick Institute, London
  • Institut für Biochemie, Universität Würzburg
  • Imperial College London
  • Institute of Infection and Immunity, St. George's University of London, London, United Kingdom.

Abstract

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.

Details

Original languageEnglish
Article numbere1006978
JournalPLoS pathogens
Volume14
Issue number5
Publication statusPublished - 18 May 2018