Plasma gelsolin attenuates acute tissue inflammation and modulates monocyte responses in experimental candidemia

Systemic Candida albicans (C. albicans) infections remain a significant cause of morbidity and mortality in immunocompromised patients, owing to both fungal proliferation and dysregulated host inflammation. Plasma gelsolin (pGSN), an actin-binding protein with immunomodulatory properties, has demonstrated protective effects in bacterial sepsis models, but its role in fungal infections remains unexplored. Here, we evaluated the impact of pGSN in an acute, 24-hour model of candidemia using athymic mice and investigated its effects on the antifungal function of primary human monocytes. Mice intravenously challenged with C. albicans developed increased 2-deoxyglucose-associated fluorescence, elevated whole-blood expression of inflammatory mediators, renal microabscesses, pulmonary pathology, and detectable circulating fungal cells. Subcutaneous administration of pGSN 12 h after infection reduced 2-deoxyglucose-associated signals in the kidneys and lungs, lowered inflammatory gene expression, decreased blood fungal CFUs, and reduced renal microabscess formation and pulmonary tissue injury. In primary human monocytes, pGSN increased fungal engagement and phagocytic uptake and generated a dose-dependent reduction in intracellular C. albicans survival. pGSN also modulated monocyte reactive radical production by increasing nitric oxide while reducing reactive oxygen species and hydrogen sulfide levels. Importantly, pGSN had no detectable direct candidacidal activity under cell-free conditions at the same concentrations, supporting a host-mediated effect. Collectively, these findings indicate that pGSN attenuates acute pathological and inflammatory responses while enhancing monocyte-mediated intracellular control of C. albicans. These results support further investigation of pGSN as a potential host-directed adjunct to antifungal therapy.