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

Dambuza, IM; Drake, T; Chapuis, A; Zhou, X; Correia, J; Taylor-Smith, L; LeGrave, N; Rasmussen, T; Fisher, MC; Bicanic, T; et al. Dambuza, IM; Drake, T; Chapuis, A; Zhou, X; Correia, J; Taylor-Smith, L; LeGrave, N; Rasmussen, T; Fisher, MC; Bicanic, T; Harrison, TS; Jaspars, M; May, RC; Brown, GD; Yuecel, R; MacCallum, DM; Ballou, ER (2018) The Cryptococcus neoformans Titan cell is an inducible and regulated morphotype underlying pathogenesis. PLoS Pathog, 14 (5). e1006978. ISSN 1553-7374 https://doi.org/10.1371/journal.ppat.1006978
SGUL Authors: Bicanic, Tihana

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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.

Item Type: Article
Additional Information: © 2018 Dambuza et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Virology, 0605 Microbiology, 1107 Immunology, 1108 Medical Microbiology
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: PLoS Pathog
ISSN: 1553-7374
Language: eng
Dates:
DateEvent
18 May 2018Published
16 March 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
BB/M014525/1Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
097377Wellcome Trusthttp://dx.doi.org/10.13039/100004440
NC/N002482/1National Centre for the Replacement, Refinement and Reduction of Animals in Researchhttp://dx.doi.org/10.13039/501100000849
102705Wellcome Trusthttp://dx.doi.org/10.13039/100004440
MR/N006364/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
PubMed ID: 29775474
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/109855
Publisher's version: https://doi.org/10.1371/journal.ppat.1006978

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