Mannan is a context-dependent shield that modifies virulence in .

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