Mannan is a context-dependent shield that modifies virulence in <i>Nakaseomyces glabratus</i>

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 <i>Candida albicans</i> results in enhanced antifungal host responses and reduced fungal virulence. However, deletions affecting mannan synthesis can lead to systemic hypervirulence for <i>Nakaseomyces glabratus</i> (formerly <i>Candida glabrata</i>) suggesting that proper mannan architecture dampens virulence for this organism. <i>N. glabratus</i> is the second leading cause of invasive and superficial candidiasis, but little is known about how the cell wall affects <i>N. glabratus</i> 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, <i>MNN10</i>, contributes to <i>N. glabratus</i> cell wall architecture, immune recognition, and virulence in reference strains BG2 and CBS138. <i>mnn10</i>Δ 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, <i>mnn10</i>Δ cells activated the β-1,3-glucan receptor in oral epithelial cells (OECs), EphA2, and caused less OEC damage than wild-type. <i>mnn10</i>Δ replication was also restricted in macrophages compared to wild-type controls. Yet, during systemic infection in <i>Galleria mellonella</i> larvae, <i>mnn10</i>Δ cells induced rapid larval melanization and BG2 <i>mnn10</i>Δ cells killed larvae significantly faster than wild-type. Thus, our data suggest that mannan plays context-dependent roles in <i>N. glabratus</i> pathogenesis, acting as a glycoshield in superficial disease models and modulating virulence during systemic infection.