The Link between Morphotype Transition and Virulence in Cryptococcus neoformans

Linqi Wang,Bing Zhai,Xiaorong Lin,Robin Charles May

doi:10.1371/journal.ppat.1002765

Abstract

Cryptococcus neoformans is a ubiquitous human fungal pathogen. This pathogen can undergo morphotype transition between the yeast and the filamentous form and such morphological transition has been implicated in virulence for decades. Morphotype transition is typically observed during mating, which is governed by pheromone signaling. Paradoxically, components specific to the pheromone signaling pathways play no or minimal direct roles in virulence. Thus, the link between morphotype transition and virulence and the underlying molecular mechanism remain elusive. Here, we demonstrate that filamentation can occur independent of pheromone signaling and mating, and both mating-dependent and mating-independent morphotype transition require the transcription factor Znf2. High expression of Znf2 is necessary and sufficient to initiate and maintain sex-independent filamentous growth under host-relevant conditions in vitro and during infection. Importantly, ZNF2 overexpression abolishes fungal virulence in murine models of cryptococcosis. Thus, Znf2 bridges the sex-independent morphotype transition and fungal pathogenicity. The impacts of Znf2 on morphological switch and pathogenicity are at least partly mediated through its effects on cell adhesion property. Cfl1, a Znf2 downstream factor, regulates morphogenesis, cell adhesion, biofilm formation, and virulence. Cfl1 is the first adhesin discovered in the phylum Basidiomycota of the Kingdom Fungi. Together with previous findings in other eukaryotic pathogens, our findings support a convergent evolution of plasticity in morphology and its impact on cell adhesion as a critical adaptive trait for pathogenesis.

Highlights

Adaptation to the host environment by many eukaryotic pathogens is often companied by transition in cellular morphology [1,2,3,4,5,6,7,8,9]
Because Cryptococcus typically grows in the yeast form and the morphological transition from the yeast form to the filamentous form appears to be coupled with mating, signaling pathways that lead to bisexual mating (a-a mating) and unisexual mating have been intensively investigated [21,22,23,24]
Cryptococcus morphological transition from the yeast form to the filamentous form is historically associated with mating, the observations that filamentation can be achieved in strains in the absence of key pheromone signaling components or meiotic genes [30,31,32,33], lead us to hypothesize that pheromone signaling pathways are not essential or sufficient for filamentation per se, but they are critical in stimulating filamentation in response to mating cues

Summary

Introduction

Adaptation to the host environment by many eukaryotic pathogens is often companied by transition in cellular morphology [1,2,3,4,5,6,7,8,9]. Because Cryptococcus typically grows in the yeast form and the morphological transition from the yeast form to the filamentous form appears to be coupled with mating, signaling pathways that lead to bisexual mating (a-a mating) and unisexual mating (mostly a-a mating) have been intensively investigated [21,22,23,24]. The roles of these signaling components in fungal pathogenicity are scrutinized in animal models. Conditions relevant to host physiology (e.g. aqueous environment, high temperatures, and high levels of CO2) are mating-suppressive, suggesting sex-independent mechanisms in orchestrating morphotype and virulence in Cryptococcus [29]

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Results

Conclusion