Rapid proliferation due to better metabolic adaptation results in full virulence of a filament-deficient Candida albicans strain

Christine Dunker,Marc Swidergall,Ilse D Jacobsen,Bianca Schulze-Richter,Melanie Polke,A Elisabeth Gressler,Tony Pawlik,M Joanna Niemiec,Katja Schubert,Thomas Dandekar,Juan P Prada Salcedo,Silvia Slesiona-Künzel,Sven Rudolphi,Ronny Martin

doi:10.1038/s41467-021-24095-8

Abstract

The ability of the fungal pathogen Candida albicans to undergo a yeast-to-hypha transition is believed to be a key virulence factor, as filaments mediate tissue damage. Here, we show that virulence is not necessarily reduced in filament-deficient strains, and the results depend on the infection model used. We generate a filament-deficient strain by deletion or repression of EED1 (known to be required for maintenance of hyphal growth). Consistent with previous studies, the strain is attenuated in damaging epithelial cells and macrophages in vitro and in a mouse model of intraperitoneal infection. However, in a mouse model of systemic infection, the strain is as virulent as the wild type when mice are challenged with intermediate infectious doses, and even more virulent when using low infectious doses. Retained virulence is associated with rapid yeast proliferation, likely the result of metabolic adaptation and improved fitness, leading to high organ fungal loads. Analyses of cytokine responses in vitro and in vivo, as well as systemic infections in immunosuppressed mice, suggest that differences in immunopathology contribute to some extent to retained virulence of the filament-deficient mutant. Our findings challenge the long-standing hypothesis that hyphae are essential for pathogenesis of systemic candidiasis by C. albicans.

Highlights

The ability of the fungal pathogen Candida albicans to undergo a yeast-to-hypha transition is believed to be a key virulence factor, as filaments mediate tissue damage
In line with the in vitro results, deletion of EED1 led to reduced damage of liver and pancreatic tissue indicated by lower serum levels of tissue-specific enzymes and lower clinical scores compared to mice infected with the wild type strain (WT; Supplementary Fig. 1)
Consistent with the role of filamentation for invasion and damage, repression or absence of EED1 in C. albicans, interfering with hyphal elongation and leading to yeast growth, resulted in significantly reduced capacity to damage epithelial cells in vitro, and reduced virulence in a murine intraperitoneal infection model in vivo the mutant was present in higher numbers than the WT in the liver

Summary

Introduction

The ability of the fungal pathogen Candida albicans to undergo a yeast-to-hypha transition is believed to be a key virulence factor, as filaments mediate tissue damage. We show that the eed1Δ/Δ mutant is fully virulent in a murine model of systemic candidiasis and confirmed this finding using a tetracycline-regulable expression system to induce or repress EED1 in C. albicans in vivo. Virulence of these filament-deficient mutants is associated with high yeast proliferation rates in vivo and enhanced growth in vitro on nutrient sources likely encountered in the host, suggesting metabolic adaptation as the underlying mechanism for retained virulence in the absence of filamentation. Analysis of host responses supports a contribution of altered immunopathology to C. albicans virulence in the absence of filamentation

Methods

Results

Conclusion