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

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.

Plasma Membrane Phosphatidylinositol-4-Phosphate Is Not Necessary for Candida albicans Viability yet Is Key for Cell Wall Integrity and Systemic Infection

“…11B ). Furthermore, we examined whether the stt4 deletion mutant could form filaments after long incubation times in serum or in kidney homogenate ( 37 ). After 6 h incubation with either serum or kidney homogenate, despite observing elongated cells, the stt4 mutant did not form hyphal filaments, compared to wild-type and complemented strains ( Fig.…”

Metabolic Adaptations During Staphylococcus aureus and Candida albicans Co-Infection

“…C. albicans mutants that are genetically locked in either morphology are attenuated during infection, highlighting the importance of the ability to switch between the yeast and the hyphal forms to cause disease ( 12 , 16 ). However, recent studies have challenged this dogma, demonstrating that certain C. albicans yeast-locked strains retain virulence in disseminated infection due to the metabolic advantages of yeast growth over hyphal growth ( 17 ). S. aureus virulence is driven by a variety of mechanisms to combat host responses and adapt to host environments.…”

Role of Cellular Metabolism during Candida-Host Interactions

“…It was believed for a long time that hyphae are essential for the pathogenicity of C. albicans during infections. This hypothesis, however, was challenged with the discovery that metabolic adaptation during systemic infections can be as important as morphological plasticity [126]. In a murine model of systemic candidiasis using the yeast-locked eed1∆/∆ mutant, virulence was retained, leading to rapid yeast proliferation, and higher fungal loads in organs such as the kidneys or liver.…”