Candida albicans (C. albicans) is the leading cause of systemic candidiasis in immunocompromised individuals and is associated with substantial mortality. As current antifungal therapies are limited by suboptimal efficacy and the emergence of resistance, improved understanding of host-pathogen interactions that govern antifungal immunity is essential for identifying new therapeutic strategies. Here, we identify MCPIP1 as a host factor that negatively regulates antifungal immune responses during lethal C. albicans infection. Integrative bioinformatic analyses of transcriptomic profiles from human peripheral blood mononuclear cells (PBMCs) exposed to C. albicans identified MCPIP1 as a macrophage-associated gene closely linked to infection-induced immune remodeling. Functional validation using in vivo and in vitro models demonstrated that MCPIP1 expression was markedly induced following systemic C. albicans infection and that MCPIP1 impaired host antifungal defenses. In a murine model of systemic candidiasis, administration of recombinant MCPIP1 exacerbated disease severity, leading to increased fungal burdens, aggravated kidney injury, and reduced host survival. Consistently, MCPIP1 suppressed macrophage-mediated phagocytosis and killing of C. albicans in vitro, indicating a direct role in regulating host-pathogen interactions at the cellular level. Mechanistically, MCPIP1 attenuated macrophage antifungal activity by suppressing p38 MAPK and ERK1/2 signaling pathways, whereas activation of these pathways restored antifungal immune function and mitigated MCPIP1-mediated immunosuppression. Together, these findings identify MCPIP1 as a key host regulator that shapes antifungal immunity during systemic C. albicans infection and highlight MCPIP1 as a potential immunomodulatory target for the treatment of invasive fungal disease.
Gao et al. (Thu,) studied this question.