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Clever surveillance system keeps yeast in check

The spectrum of human diseases (mycoses) caused by fungi ranges from trivial nail infections to life-threatening systemic infections. The latter are mainly caused by Candida albicans. The dermatologist Prof. Dr. med. Martin Schaller from Tübingen is investigating how this fungus, which is actually part of the normal microbial flora of humans, becomes a pathogen. At the same time, he is looking into the role the patient’s immune system plays in this process.

Professor Dr. med. Martin Schaller, Assistant Medical Director at the University Skin Clinic in Tübingen. © private

Whilst Schaller comes across the entire range of mycoses in his job as assistant medical director of the Skin Hospital at the University of Tübingen, his scientific work has for quite some time exclusively focused on the yeast Candida albicans. C. albicans has an exceptional position in dermatology as the fungus can exist on human skin and mucosas for many decades without leading to visible symptoms of disease. "The exclusive identification of Candida in the oral cavity, on the genital mucosa or stools does not make it necessary to treat the infection," said Schaller adding that the fungus might also be associated with a previously unknown benefit for its host.

However, when the patients reveal typical symptoms such as white patches on the mouth mucosa (thrush), then it becomes crucial to identify which species of the fungus it is. Candida albicans infections can become life threatening for people whose immune systems have been compromised as a result of chemotherapy, organ transplantation or HIV infection. In such cases, the microorganisms can easily enter lower layers of tissue, where they enter the blood circulation and from there they can spread around the entire body - often with fatal consequences.

Model system with a view for details

Schaller and his team of researchers are interested in all the factors that turn harmless Candida infections into local or systemic infections. “Our primary goal is to use suitable model systems to characterise the interaction of the fungus with the host’s immune defence,” said Schaller. Schaller uses a three-dimensional culture system consisting of epithelial cells isolated from the mouth mucosa.

Schaller prefers the in vitro model to animal experiments for ethical as well as scientific reasons. “In contrast to humans, Candida albicans is not part of the natural microbial flora in mice,” said the scientist explaining that it is difficult to colonise and infect the mice with Candida albicans. “One needs to really torture the mice in order to make them develop candidosis,” said Schaller explaining why he prefers in vitro systems to animals. Commercially available in vitro systems also have the advantage that the interaction of the fungi with the epithelial cells on the one hand and the cells of the immune system on the other hand can be investigated a lot more specifically.

Three-dimensional culture systems are excellently suited for infection studies with Candida albicans. The fluorescence microscope image shows: TLR4 (red), Candida albicans (green) and the cell nuclei of the epithelium (blue). Fig. (a) and (b) show the basis value of TLR4 expression in the epithelial tissue, with and without the addition of white blood cells with polymorphous nuclei (arrow). Fig. (c) shows that C. albicans downregulates the epithelial TLR4 expression. The presence of white blood cells with polymorphous nuclei (Fig. d), leads to the huge upregulation of TLR4 expression, which is associated with a protective effect. © Schaller

Difficult immune response

”It is now known that epithelial cells of the skin and mucosas continuously secrete peptides that have an antimicrobial effect,” said Schaller. “These peptides can directly kill the yeasts and prevent Candida growing everywhere in the body.” If the fungus becomes more virulent and hence more aggressive as the result of a reaction to certain environmental factors (e.g., the administration of antibiotics), this leads to the immediate upregulation of these protective peptides.

The epithelial cells of Schaller’s model release immunoregulatory cytokines when they are damaged by Candida. The cytokines attract a specific fraction of white blood cells (the neutrophile granulocytes) to the site of infection. In turn, the granulocytes trigger the elevated production of certain factors (e.g., toll-like receptors; TLR). TLRs are part of the innate immune response which mounts an immediate defence against pathogens, by inducing for example the production of antimicrobial peptides in neutrophile granulocytes,” said Schaller.

Close connection of clinical application and science

The white blood cells usually suffer considerably during chemotherapy or treatment with immunosuppressive medicine. “Our results are now giving us explanations as to why immunocompromised individuals in particular develop candidoses,” said the dermatologist who regrets that the number of clinicians active in basic mycological research is falling. “I am practically the only clinician in the DFG’s (German Research Foundation) priority programme who is working on the “colonisation and infection of human pathogenic fungi”,” said Schaller who finds that the close links between clinical application, laboratory diagnostics and scientific work are very fertile. “The fact that I have to deal with individual disease patterns virtually every day gives me specific stimuli non-clinicians who rarely see patients just would not have.”

Further information:

University Skin Clinic Tübingen
Prof. Dr. med. Martin Schaller
Liebermeisterstraße 25
72076 Tübingen
Tel.: +49 (0)7071 29-83767
Fax: +49 (0)7071 29-5113
E-mail: martin.schaller(at)med.uni-tuebingen.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/clever-surveillance-system-keeps-yeast-in-check