Neutrophil-Derived Vesicles Help Some Candida Cells Evade Capture

Immune cells sent to destroy Candida albicans may inadvertently be handing some of the fungus a way to slip past them, according to a new study published in the Journal of Extracellular Vesicles. Candida albicans normally lives harmlessly on the skin and mucous membranes of many people, but if it enters the bloodstream it can spread through the body and become especially dangerous for people with weakened immune systems. Neutrophils, white blood cells that recognize pathogens, engulf them, and destroy them internally, are among the immune system's main defenses against such invasions.

To study how neutrophils and Candida albicans interact, a team led by researchers from Leibniz-HKI added the fungus to blood drawn from healthy donors. “We noticed that a small proportion of the fungal cells consistently remained free in the blood, even though there were enough immune cells present to take them up,” says study leader Oliver Kurzai. What surprised the team was where that protection seemed to come from. “The fact that components of the immune cells themselves contribute to this effect was a surprising observation for us,” Kurzai adds.

Looking for an explanation, the researchers found proteins on the surface of the free-floating fungal cells that had originally belonged to neutrophils. The trail led to extracellular vesicles, tiny membrane-bound packages that cells release into their surroundings carrying proteins and other molecules. Neutrophils release these vesicles when they encounter pathogens, and the team showed that the vesicles attach directly to Candida albicans, depositing immune-cell components onto the fungal surface.

What happens next is counterintuitive: despite carrying numerous antimicrobial molecules, the vesicles did not slow fungal growth. Instead, fungal cells that had picked up vesicles were taken up less often by neutrophils, an effect the team observed both with isolated immune cells and in whole blood.

This isn’t a trick the fungus is playing. Candida albicans is known to actively evade immune defenses in other ways, but this isn’t one of them, the researchers note; the effect showed up even with dead fungal cells, and it doesn’t offer full protection. “This is not an all-or-nothing effect: the vesicles do not completely prevent immune cells from taking up the fungus, but they shift the odds in its favor, leaving a larger proportion of fungal cells outside the immune cells,” explains Kerstin Hünniger-Ast, co-author of the study. “It is an advantage that Candida albicans does not appear to bring about itself. Rather, it arises as a consequence of our own immune response.”

Exactly why the vesicles make fungal cells harder to engulf is still unclear. The researchers propose two possibilities: the attached vesicles might physically cover structures on the fungal cell wall that immune cells rely on to recognize it, or the transferred host proteins might make the fungal surface look less foreign, letting it slip past immune surveillance under what amounts to a borrowed disguise.

The results add a new layer to what’s known about extracellular vesicles in fungal infection. Earlier work had shown that neutrophil-derived vesicles can inhibit growth of the mold Aspergillus fumigatus; with Candida albicans, the same kind of vesicle leaves growth untouched but instead helps the fungus dodge capture. Whether this same mechanism plays out in patients with Candida bloodstream infections, or in infections caused by other pathogens, is a question the researchers say still needs to be answered.