Meteorin-like is associated with poor outcome in invasive candidiasis in mouse models and in humans

Invasive candidiasis is a leading cause of nosocomial bloodstream infection associated with high mortality, and there is a pressing need to develop biomarker-guided antifungal therapy to improve clinical outcomes. Meteorin-like (METRNL) is a cytokine that can act as a high-affinity ligand for the stem cell factor receptor KIT; however, the functional role of METRNL in fungal infection remains unclear. Here, we found that METRNL acts as a disease-promoting immune checkpoint to facilitate invasive Candida albicans (C. albicans) infection. Mice deficient in METRNL were refractory to a lethal systemic infection with C. albicans. Treatment with a METRNL blocking antibody protected mice from invasive C. albicans infection, whereas treatment with recombinant METRNL or overexpression of endogenous METRNL dampened fungal clearance and aggravated disease mortality but not in mice with macrophage-specific deletion of KIT. The METRNL-KIT axis decreased dectin-1 expression and impaired fungal phagocytosis and killing capacity in macrophages, which was dependent on signal transducer and activator of transcription 3 signaling, thereby negatively regulating host antifungal immunity. In two independent cohorts, patients with candidemia had elevated circulating METRNL concentrations compared with patients with bacteremia or healthy volunteers. In both cohorts, a higher circulating METRNL concentration was associated with poor survival. Therefore, our study provides mechanistic and translational insights into how METRNL orchestrates macrophage-dependent antifungal immunity, implying that a potential theranostic approach involving blood-circulating METRNL-guided patient stratification and targeted therapy of blocking METRNL may help improve the management of human fungal disease through a precision medicine strategy.