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Add as preferred source Researchers have developed a potential new approach against the highly drug-resistant hospital fungus Candida auris. They discovered that a synthetic sugar molecule that is a natural part of the fungus's cell wall, but is not present in humans, could underpin a future vaccine, develop protective antibodies and form the basis of a prototype rapid diagnostic test.
Candida auris is an emerging, multidrug-resistant fungal pathogen that is spreading particularly in health care facilities. It is particularly dangerous in people with weakened immune systems. First discovered in Japan in 2009, it has now spread worldwide. To date, neither vaccines nor rapid diagnostic methods are available for C. auris.
Now, in research published in the journal Angewandte Chemie International Edition, a team including the Max Planck Institute of Colloids and Interfaces, Freie Universität Berlin and the MRC Center for Medical Mycology at the University of Exeter has identified a sugar structure that corresponds to a component of the C. auris surface. The molecule is a man-made version of the same structure found in the fungus, and it can be specifically recognized by the immune system, binding in a way that helps direct the immune response specifically against the fungus.
The sugar structure serves as the basis for a vaccine candidate and protective antibodies. In addition, the researchers used one of these antibodies to develop a prototype rapid test to detect multiple Candida species in a lateral flow device format—similar to those used to detect COVID.
"Through chemical synthesis, we can precisely replicate individual sugar structures of the fungus and determine which ones the immune system recognizes," says Professor Peter H. Seeberger, director at the Max Planck Institute and co-author of the study. "This opens up the possibility for us to find a strategy to combat Candida auris."
Developing a vaccine against the yeast C. auris is a particular challenge. Fungal cell walls consist largely of complex sugar structures. These do not exist as uniform structures but differ in length and linkage. It is therefore not easy to determine which of these structures the immune system recognizes, triggering a protective immune response.
For this reason, the researchers chemically synthesized the sugar structures in the laboratory rather than purified them from the fungal cell wall. This allowed them to study individual molecules with precisely defined composition and structure. In the process, they identified a promising molecule consisting of four linked sugar building blocks that corresponds to the sugars on the surface of the fungus. It is a β-mannan tetrasaccharide that is recognized by antibodies.
To enable the immune system to specifically recognize this particular sugar structure, the sugar was linked to a carrier protein. The combination of sugar and protein is called a glycoconjugate and helps trigger a targeted immune response against the sugar structure.
In the study, an infection model using mice showed that vaccination with the glycoconjugate triggered a specific immune response. The animals produced antibodies that specifically recognized the synthetic sugar structure. In the vaccinated animals, the fungal load in the kidneys and spleen was reduced following infection.
"Our results show that a single, chemically defined sugar structure is sufficient to elicit a targeted immune response against Candida auris and to limit the infection in the animal model," Seeberger says. "This provides important preclinical evidence of efficacy for this vaccine approach."
The researchers also developed an antibody that specifically recognizes the sugar structure. In the animal model, this antibody likewise protected the mice from infection, resulting in a reduced fungal load in the spleen of passively immunized mice.
But the sugar structure can do even more: The antibodies can also be used to detect the fungus. The researchers used them to develop a rapid test based on a principle similar to that of a pregnancy or COVID-19 rapid test. The test detects structures on the surface of C. auris and could potentially enable rapid identification of the fungus.
"The fact that the same sugar structure can be used for a vaccine as well as for antibodies and a diagnostic test is particularly interesting. We are thus demonstrating the potential that chemically defined glycans have for infectious disease medicine," Seeberger says.
The researchers have achieved a series of successes: Using a single, chemically defined sugar molecule, they were able to develop a vaccine candidate, identify protective antibodies and produce a prototype rapid test. The results combine vaccination, passive immunization and diagnostics based on a single defined sugar structure.
The findings build on earlier work by the research team, in which synthetic sugar structures from Candida were produced and examined for their immunological recognition. The current study takes this approach a step further.
The approaches developed are still in preclinical development. The vaccine candidate and the antibodies have so far been tested in animal models. The rapid test is also initially a prototype. Further studies are required before it can potentially be used in humans.
Professor Neil Gow, of the University of Exeter's MRC Center for Medical Mycology, said, "The world has become increasingly anxious about the emergence of Candida auris as a drug-resistant and persistent fungal pathogen of humans. It has been exciting to be part of this collaboration to understand what parts of the C. auris yeast surface act as a signature of infection and can be used to design immunotherapies and diagnostic tests."
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