Mannan is a context-dependent shield that modifies virulence in Nakaseomyces glabratus

Fungal-host interaction outcomes are influenced by how the host recognizes fungal cell wall components. Mannan is a major cell wall carbohydrate and can be a glycoshield that blocks the inner cell wall β-1,3-glucan from activating pro-inflammatory immune responses. Disturbing this glycoshield in Candida albicans results in enhanced antifungal host responses and reduced fungal virulence. However, deletions affecting mannan synthesis can lead to systemic hypervirulence for Nakaseomyces glabratus (formerly Candida glabrata) suggesting that proper mannan architecture dampens virulence for this organism. N. glabratus is the second leading cause of invasive and superficial candidiasis, but little is known about how the cell wall affects N. glabratus pathogenesis. In order to better understand the importance of these species-specific cell wall adaptations in infection, we set out to investigate how the mannan polymerase II complex gene, MNN10, contributes to N. glabratus cell wall architecture, immune recognition, and virulence in reference strains BG2 and CBS138. mnn10Δ cells had thinner inner and outer cell wall layers and elevated mannan, chitin, and β-1,3-glucan exposure compared to wild-type cells. Consistent with these observations, mnn10Δ cells activated the β-1,3-glucan receptor in oral epithelial cells (OECs), EphA2, and caused less OEC damage than wild-type. mnn10Δ replication was also restricted in macrophages compared to wild-type controls. Yet, during systemic infection in Galleria mellonella larvae, mnn10Δ cells induced rapid larval melanization and BG2 mnn10Δ cells killed larvae significantly faster than wild-type. Thus, our data suggest that mannan plays context-dependent roles in N. glabratus pathogenesis, acting as a glycoshield in superficial disease models and modulating virulence during systemic infection.