Candida auris emerged as an important fungal pathogen in 2009, when the previously unknown fungus was discovered in the infected ear of a seventy-year-old Japanese woman. Where C. auris suddenly came from was not clear, but soon after that, different strains appeared all over the world. It turned out to be a persistent, difficult to control fungus.

Since then, the fungus has spread across six continents as a causative microorganism of hospital-acquired infections. It remains challenging on many fronts, not only difficult to diagnose but also resistant to many commonly used antifungal drugs.

Now, an international team led by researchers from Radboud University Medical Center in the Netherlands, has discovered that the human immune system recognizes the fungus well. The team integrated transcriptional and functional immune-cell profiling to uncover innate defense mechanisms against C. auris.

The work is published in an article in Nature Microbiology titled,  “Transcriptional and functional insights into the host immune response against the emerging fungal pathogen Candida auris.

“We started to investigate C. auris with international colleagues because there was virtually nothing known about this fungus,” said Mariolina Bruno, a PhD candidate in the Radboud University Medical Center’s department of internal medicine. Their findings showed, according to Bruno, that, “A well-functioning immune system recognizes the fungus clearly and can control it well.” But, the fungus is especially dangerous for people with compromised immunity.

A careful study of the human immune response to the C. auris infection demonstrated that specific components of the cell wall of the fungus play an essential role in this recognition. David Williams, PhD, the Carroll H. Long chair of excellence for surgical research at East Tennessee State University said: “These are unique structures that you do not encounter with other fungi. Those specific chemical structures stimulate the immune system enough to take action and clear the fungus.”

The authors write that C. auris induces “a specific transcriptome in human mononuclear cells, a stronger cytokine response compared with Candida albicans, but a lower macrophage lysis capacity.”

They noted that C. auris-induced innate immune activation is “mediated through the recognition of C-type lectin receptors, mainly elicited by structurally unique C. auris mannoproteins.”

The fact that C. auris is considered a serious and emerging infectious disease is mainly due to its resistance to many disinfectants and fungicides. People with an invasive C. auris fungal infection have a thirty to sixty percent chance of dying, precisely because of the immunity of the fungus to many fungicides. Alistair Brown, PhD, professor at the MRC Centre for Medical Mycology, University of Exeter, noted that, “Our research not only shows that these cell wall components are important for the detection by the immune system, but also that they are indispensable to the fungus. Drugs that selectively block the production and operation of these components are currently being investigated for safety and effectiveness. Perhaps one of these is the ideal candidate to tackle the fungus.”

Since these cell wall components are indispensable to C. auris, the risk of resistance to such a new drug is small. In order to develop resistance, the fungus must at least remain alive so that it can gradually adapt to the new drug.

Candida auris is related to the much better-known Candida albicans, which can cause vaginal fungal infections. In the study, C. albicans has therefore served as comparison material. Bruno noted that, “On the one hand, we see that C auris evokes a better immunity reaction than C. albicans. On the other hand, C. auris appears less pathogenic, but once in the bloodstream, both fungi are usually life-threatening.”

What makes the problem even worse is that C. auris is not so easy to identify. This makes it easy to confuse with other fungi, which can lead to a delay in treatment. Jacques Meis, MD, PhD, consultant, clinical microbiology and infectious diseases, Canisius-Wilhelmina Hospital, Nijmegen said, “You should determine the fungi type on a molecular level, enabling you to immediately see which fungus you are dealing with, but not every laboratory has the facilities for that.” Earlier this year, he and Paul Verweij, MD, professor of clinical mycology at Radboud University Medical Center, called for the nation-wide monitoring of serious fungal infections to gain a better understanding of the burden of disease and mortality rates.

The team’s findings suggest that, in vivo experimental models of disseminated candidiasis, “C. auris was less virulent than C. albicans.” Collectively, the authors noted, “These results demonstrate that C. auris is a strong inducer of innate host defense, and identify possible targets for adjuvant immunotherapy.”

The question why C. auris suddenly appeared in 2009 has still not been answered. The fungus was not found in stored patient material from previous years, so it seems to be a new or mutated fungus. It has been hypothesized that the increase in temperatures caused by global warming may play a role.

“An interesting point of view,” said Bruno, “but without further evidence, it is as yet highly speculative. Apart from the actual origin history or ‘birth’ of C. auris, the article in Nature Microbiology provides information on how the interaction between humans and the fungus C. auris occurs: how the fungus stimulates the immune system, what C. auris‘ pharmacological Achilles heel is, and what the opportunities for immunotherapy are.”

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