Control of β-glucan exposure by the endo-1,3-glucanase Eng1 in Candida albicans modulates virulence

Candida albicans is a major opportunistic pathogen of humans. It can grow as morphologically distinct yeast, pseudohyphae and hyphae, and the ability to switch reversibly among different forms is critical for its virulence. The relationship between morphogenesis and innate immune recognition is not quite clear. Dectin-1 is a major C-type lectin receptor that recognizes beta-glucan in the fungal cell wall. C. albicans beta-glucan is usually masked by the outer mannan layer of the cell wall. Whether and how beta-glucan masking is differentially regulated during hyphal morphogenesis is not fully understood. Here we show that the endo-1,3-glucanase Eng1 is differentially expressed in yeast, and together with Yeast Wall Protein 1 (Ywp1), regulates beta-glucan exposure and Dectin-1-dependent immune activation of macrophage by yeast cells. ENG1 deletion results in enhanced Dectin-1 binding at the septa of yeast cells; while eng1 ywp1 yeast cells show strong overall Dectin-1 binding similar to hyphae of wild-type and eng1 mutants. Correlatively, hyphae of wild-type and eng1 induced similar levels of cytokines in macrophage. ENG1 expression and Eng1-mediated beta-glucan trimming are also regulated by antifungal drugs, lactate and N-acetylglucosamine. Deletion of ENG1 modulates virulence in the mouse model of hematogenously disseminated candidiasis in a Dectin-1-dependent manner. The eng1 mutant exhibited attenuated lethality in male mice, but enhanced lethality in female mice, which was associated with a stronger renal immune response and lower fungal burden. Thus, Eng1-regulated beta-glucan exposure in yeast cells modulates the balance between immune protection and immunopathogenesis during disseminated candidiasis. Author summaryCandida albicans is a major cause of invasive candidiasis, which has a high mortality rate. It is a constituent of the human microbiome and found in the gastrointestinal and genitourinary tracts of most healthy individuals. C. albicans is able to switch reversibly between yeast and hyphae in response to environmental cues, and the ability to switch is essential for virulence. The innate immune response is critical for host defense against fungal infections. However, the relationships between morphogenesis, host immune recognition and immune protection are not fully understood for C. albicans. This study shows that beta-glucan is masked by two highly expressed yeast proteins, the endo-1,3-beta-glucanase Eng1 and Yeast Wall Protein 1 Ywp1. beta-glucan is exposed during yeast-to-hypha transition. Eng1 level is also dynamically regulated in response to different carbon sources and antifungal drugs. The eng1 mutant modulates virulence in the mouse model of hematogenously disseminated candidiasis in a sex and Dectin-1-dependent manner. Our data reveal that the level of beta-glucan exposure in C. albicans is highly controlled to modulate the balance between immune protection and immunopathogenesis during disseminated candidiasis.

Automated summary

Candida albicans, a major opportunistic pathogen, can switch between different forms and regulate immune recognition during morphogenesis. This study reveals that two highly expressed yeast proteins, Eng1 and Ywp1, mask beta-glucan in the cell wall, but beta-glucan is exposed during yeast-to-hypha transition. The expression of Eng1 is dynamically regulated in response to different carbon sources and antifungal drugs. The eng1 mutant modulates virulence in a sex and Dectin-1-dependent manner in a mouse model of disseminated candidiasis. These findings highlight the importance of beta-glucan exposure in modulating the balance between immune protection and immunopathogenesis during candidiasis.