The role of neutrophil-derived EVs in promoting Candida albicans escape from phagocytosis

Candida albicans is a common commensal fungus that can cause life-threatening invasive infections in immunocompromised individuals and is a leading cause of hospital-acquired sepsis. Neutrophils represent the primary effector cells responsible for the uptake of C. albicans, and play a crucial role in the clearance of fungal cells from the bloodstream. However, previous studies using an ex vivo human whole-blood model have shown that a substantial proportion of C. albicans cells remains extracellular through unknown mechanisms. This evasion appears to be independent of the intrinsic pathogenic activity of the fungal cells and instead depends on the activation state of neutrophils and monocytes. Simulations using a virtual infection model suggested that host-related factors can significantly influence immune evasion. A defining feature of the emerging extracellular fungal population was the time-dependent acquisition of canonical neutrophil surface markers and Annexin V on the C. albicans cell surface. Mechanistically, we found that the transfer of host proteins onto C. albicans was mediated by neutrophil-derived extracellular vesicles (EVs) binding to fungal cells, which was associated with decreased uptake by phagocytes. To quantitatively evaluate this phenomenon, we extended our virtual infection model to introduce an extracellular population of C. albicans bound by neutrophil-derived EVs. Simulations confirmed that EV-bound fungal cells are phagocytosed ~50% less efficiently than cells lacking neutrophil surface markers, based on parameter estimates from experimental data. This reduction in uptake supports the hypothesis that the acquisition of host-derived surface features significantly impairs immune recognition and clearance. These findings point to a previously unrecognized mechanism of immune modulation that may enable the persistence of a viable, extracellular C. albicans population in the bloodstream.