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Neutrophils are among the immune system’s most important first responders. These white blood cells can quickly recognize, engulf, and destroy invading microorganisms, including the fungal pathogen Candida albicans.
However, some C. albicans cells are able to remain alive in human blood even when neutrophils are present. Researchers at the Julius Maximilians University of Würzburg have now identified an unexpected role for extracellular vesicles, or EVs, released by neutrophils in helping these fungal cells avoid clearance.
Extracellular vesicles carry antimicrobial proteins
Extracellular vesicles are small membrane-bound particles released by cells. They can carry proteins, lipids, nucleic acids, and other molecules between cells, making them an important part of biological communication.
The researchers found that neutrophil-derived EVs contained several proteins associated with immune defense. These included antimicrobial proteins and neutrophil surface markers such as CD66b, CD45, and CD63, along with complement receptors CR1, CR3, and CR4.
At first glance, vesicles carrying these immune molecules might be expected to help destroy fungal cells. Instead, the researchers observed something more complicated.
EVs attach to Candida albicans
The neutrophil-derived extracellular vesicles preferentially attached to C. albicans cells. This interaction depended in part on the complement system, a collection of blood proteins that helps immune cells recognize and eliminate microorganisms.
Blocking CD11b, part of the complement receptor CR3, reduced EV attachment, suggesting that CR3 contributes to the interaction between the vesicles and fungal cells.
Despite carrying antimicrobial proteins, the extracellular vesicles did not significantly slow fungal growth.
Instead, fungal cells coated with neutrophil-derived EVs were less likely to be engulfed by neutrophils.
A surprising effect on phagocytosis
Phagocytosis is the process by which immune cells surround, ingest, and destroy microbes. It is one of the main ways neutrophils eliminate C. albicans from the bloodstream.
The researchers found that EV-coated fungal cells were phagocytosed less efficiently, both in experiments using purified neutrophils and in whole human blood.
This suggests that the extracellular vesicles may act as an unexpected protective coating. Rather than directly killing the fungus, their attachment may interfere with the ability of neutrophils to recognize or engulf some fungal cells.
The findings add another layer to what is already known about extracellular vesicles at the host-pathogen interface. Previous research has shown that both immune cells and fungi can release EVs that influence inflammation, immune signaling, and microbial survival.
Extracellular vesicles can have more than one role
One of the most important implications is that extracellular vesicles do not necessarily have a simple beneficial or harmful function.
Neutrophil EVs can contain molecules that would normally be considered antimicrobial, yet their physical association with C. albicans was linked to reduced phagocytosis and continued fungal survival.
Understanding this interaction may help researchers better explain how a small population of C. albicans can remain extracellular and viable even in the presence of an active immune response.
More broadly, the results highlight the complexity of extracellular vesicle biology during infection. The same vesicles that carry immune effector molecules may also influence how pathogens are recognized, attacked, or protected within the bloodstream.
