Loss of Fgr41 in <i>Candida albicans</i> attenuates virulence and increases proinflammatory immune responses in a manner that is dependent on β(1,3)-glucan but not dectin-1

β(1, 3)-glucan is an essential cell wall polysaccharide in the fungal pathogen <i>Candida albicans</i> and is also an important immunogenic epitope for host recognition. This polymer is normally masked from immune recognition by a layer of mannosylated glycoproteins on the outer cell wall, but it can become exposed in certain conditions. Prior work showed that the putative secretory protein Fgr41 is downregulated in conditions that increase β(1, 3)-glucan exposure, including caspofungin treatment or activation of the Cek1 MAP kinase pathway. Disruption of <i>FGR41</i> increases <i>C. albicans</i> β(1, 3)-glucan unmasking and reduces kidney fungal burden in murine systemic infections in an immune-dependent manner. We tested the impact of <i>FGR41</i> on immune evasion by measuring tumor necrosis factor alpha (TNF-α) secretion from murine macrophages <i>in vitro</i>. The <i>fgr41Δ/Δ</i> mutant elicited ~4 times more TNF-α from macrophages than wild-type. Antibody neutralization of dectin-1 did not significantly reduce TNF-α released from macrophages challenged with the <i>fgr41Δ/Δ</i> strain. However, an inhibitory, soluble β-glucan (laminarin) significantly reduced <i>fgr41Δ/Δ-</i>induced stimulation, suggesting that macrophage recognition of the <i>fgr41Δ/Δ</i> mutant is driven by the detection of exposed β(1, 3)-glucan by another receptor. When assessed <i>in vivo</i>, the attenuated virulence observed for the <i>fgr41Δ/Δ</i> strain in wild-type mice was similar in dectin-1^-/- mice, indicating that a non-dectin-1 mechanism recognizes the <i>fgr41Δ/Δ</i> mutant <i>in vivo</i>. Genetic data suggest that the role of <i>FGR41</i> in immune evasion is partially dependent on the cell wall β-glucanase <i>ENG1</i>. Overexpression of <i>ENG1</i> partially suppresses <i>fgr41Δ/Δ-</i>induced unmasking and TNF-α stimulation, but the opposite is not true, indicating that these proteins may work together.