Adhesive force of an infectious fungal pathogen decoded

Candida auris

The disease-causing yeast Candida auris is particularly robust and resistant to many medications. © selvanegra/ iStock

Since its discovery in 2009, the yeast Candida auris has become a growing healthcare problem. It colonizes various surfaces - from human skin to medical devices - and is resistant to many drugs. For people with weakened immune systems, an infection can be fatal. Researchers have now unlocked the secret of the mushroom's extraordinary adhesive power. Accordingly, a previously unknown adhesive protein ensures particularly stable binding to surfaces and is crucial for the virulence of the fungus.

The multi-resistant pathogen Candida auris causes dangerous hospital infections. The fungus was first discovered in 2009 in the ear canal of a Japanese patient where it caused an ear infection. The name “auris” comes from the Latin word for ear. While it is harmless to healthy people, the fungus causes life-threatening infections in immunocompromised people. It can spread to large parts of the body via the bloodstream and damage the internal organs. Candida auris is resistant to most medications used to combat fungal infections. An additional problem: The yeast adheres exceptionally well to a variety of surfaces and even defies some disinfectants. In this way, it can, for example, settle on catheters and other medical devices and spread in this way.

Searching for traces in the genome

To find out what gives Candida auris its adhesive power, a team led by Darian Santana from the University of Michigan set out to search for clues. The researchers first examined the usual suspects: so-called adhesin proteins, which are already known from other yeast fungi. These proteins sit on the outside of bacteria and fungi and allow them to attach to surfaces. Using genetic engineering methods, Santana and his team gradually deleted every single instruction manual for the known adhesive proteins from the Candida auris genome and tested for each mutant how well it still adheres to surfaces.

The researchers were able to remove eleven out of twelve of the adhesin proteins known from other Candida species without reducing the adhesive strength of Candida auris. “Only deleting the adhesin protein called IFF4109 resulted in a slightly lower adhesive force, but without completely preventing attachment to surfaces,” report the researchers. Another adhesive protein that had not previously been detected or described in other species had to be responsible for the adhesive force.

Binding like mussels and barnacles

In search of this mysterious protein, Santana and his team searched the entire genome of Candida auris - and finally discovered a novel adhesin, which they named surface colonization factor (SCF1). “The new adhesin is only present in C. auris, so we don't know where it came from evolutionarily,” says Santana colleague Teresa O'Meara. Unlike the previously known fungal adhesins, which only adhere with the help of comparatively weak hydrophobic interactions, SCF1 forms particularly strong bonds, so-called cation-pi bonds.

"Much of the literature about these types of bonds in nature comes from people trying to develop an adhesive that sticks underwater," explains O'Meara. In fact, the adhesive principle of SCF1 is more similar to that of mussels and barnacles. “In nature, Candida auris has been isolated from coastal wetlands in the Andaman Islands and from a Colombian estuary,” explains the research team. “This suggests an original marine habitat, and this ecological niche could have exerted corresponding selection pressure on the adhesion mechanisms.”

Adhesive protein influences virulence

In experiments with mice, rats and human skin samples, the team demonstrated that SCF1 is indeed responsible for the yeast's strong adhesion and virulence. If they infected immunocompromised mice intravenously with the fungus, serious damage to the heart and kidneys occurred within a week. Mutants of the fungus without SCF1, on the other hand, caused significantly less damage to the organs. Mutants in which SCF1 was expressed particularly strongly had a correspondingly more destructive effect. In further experiments, all mice that were infected with the virulent variant of Candida auris died within twelve days. Of the animals that were infected with a mutant without SCF1, eight out of ten were still alive after three weeks.

"So far we don't know why this adhesin is required to cause disease," says O'Meara. “Perhaps it is necessary for attachment to blood vessels, or perhaps it alters host-receptor interactions, as is the case with the related fungus Candida albicans. But we don’t know that yet in this case.” The team would therefore like to further investigate the connections between SCF1 and the virulence of Candida auris in future studies. This could possibly lead to new approaches for targeted therapy against the fungal disease.

Source: Darian Santana (University of Michigan, USA) et al., Science, doi: 10.1126/science.adf8972

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