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 <i>Candida albicans</i> (<i>C. albicans</i>) infection. Mice deficient in METRNL were refractory to a lethal systemic infection with <i>C. albicans.</i> Treatment with a METRNL blocking antibody protected mice from invasive <i>C. albicans</i> 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.