Plasmids used in this study.

Invasive fungal infections are a leading cause of mortality and morbidity in patients with severely impaired host defenses, while treatment options remain limited. Fatty acid synthase (FASN), the key enzyme regulating de novo biosynthesis of fatty acids, is crucial for the lethal infection of fungi; however, its pathogenic mechanism is still far from clear. Here, we identified the α subunit of FASN as a potential immunotherapeutic target against systemic Candida albicans infection. The avirulence of the encoded gene (FAS2) -deleted mutant in a mouse model of systemic candidiasis is not due to its fitness defects, because sufficient exogenous fatty acids in serum can overcome FASN inhibition. However, the FAS2-deleted mutant displays increased circulating innate immune responses and enhances activated neutrophil fungicidal activity through the unmasking of immunogenic cell wall epitopes via the Rho-1 dependent Mkc1-MAPK signaling pathway, which facilitates fungal clearance, reduces renal tissue damage and inflammatory cell infiltration, ultimately lowers fungal pathogenicity. Priming with the FAS2-deleted mutant provided significant protection against subsequent lethal infection with wild-type C. albicans in mice as early as one week, and it was well-tolerated with limited toxicity. Our findings indicate that the FASN-α subunit plays key roles in the regulation of neutrophil-associated antifungal immunity and could be a potential target for immunotherapeutic intervention.