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Potential new treatment to combat lethal fungal infections

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Candida albicans

 (Vienna, 18 July 2016) Viennese researchers from the IMBA (Institute of Molecular Biotechnology) and the Max F. Perutz Laboratories (MFPL) at MedUni Vienna and the University of Vienna have discovered a completely new mechanism that could lead to a treatment for life-threatening fungal infections: blockading the CBL-B enzyme boosts the immune response to the pathogenic fungus Candida albicans. When CBL-B was "switched off" in an animal model, the endogenous defence mechanisms were activated and an invasive, often lethal infection was fended off.

Fungal infections are the commonest infections worldwide – over the course of their lifetime, one in four people will suffer from an unpleasant infection of the skin or mucous membranes. However, what is perhaps less well known is that fungal infections claim around 1.5 million human lives every year. In most cases, an attack of the monocellular yeast fungus Candida albicans is harmless and is easily treated. However, if our immune system fails to recognize the pathogen, the fungus can spread throughout the whole body and can lead to a dangerous form of blood poisoning, fungal sepsis. Such so-called invasive infections are fatal in 50% of cases.

Fungal infections are becoming increasingly significant in everyday clinical practice for people with a compromised immune system. Many of the new treatments of modern medicine, such as organ transplants or cancer treatments, are often associated with short to long-term weakening or damage to the immune system. Unfortunately, in this weakened state, an infection with the common yeast fungus can very quickly become life-threatening. Up until now, there have been no effective treatments for combating such an infection at this advanced stage.

Immune response: Nipping it in the bud

Scientists in Vienna have now discovered how the immune system successfully repels an invasion of Candida albicans. The function of the human immune system is to unmask invaders. Viruses, bacteria and fungal pathogens are recognized by so-called "immunoreceptors", by means of their typical signature, on the outer wall of the cell. These receptors dock onto the outer wall of the invader and alert and activate the body's own defence cells, which are then able to kill off the pathogen. Molecular biologists Gerald Wirnsberger and Florian Zwolanek from the working groups led by Josef Penninger (IMBA) and Karl Kuchlers (MFPL) have now been able to show that the enzyme CBL-B and a kinase called SYK play an important role in the immune response to candida. SYK amplifies the signal for targeted defence against the fungal pathogen, while CBL-B attenuates transmission of the signal for the immune response and ultimately switches it off completely.

In a next step, the researchers developed a completely new type of protein, a so-called "inhibitor", to specifically inhibit CBL-B in mice. This enabled an invasive candida infection to be successfully repelled, while mice, in which CBL-B was active, very quickly succumbed to a systemic candida infection. The results of the study were published in Nature Medicine and could pave the way for a new treatment against invasive fungal infections.

"Our research marks the first milestone on the way to a completely new type of treatment for Candida albicans. For the very first time, we succeeded in directing the immune response, which is modulated by CBL-B. This novel method of treatment could turn out to be very successful clinically, especially in combination with existing methods of treatment, which are aimed at inhibiting growth of the fungus," says Professor Karl Kuchler from MedUni Vienna, speaking about the results of the study.

Even Professor Josef Penninger, scientific director of the IMBA, is surprised: "It is becoming increasingly important for the medicine of tomorrow to solve the molecular puzzles of the immune response, so that we are able to strengthen the body's own protective shield against a specific invader. We have now succeeded in doing this for the frequently fatal fungus Candida albicans."

“Inhibition of CBLB protects from lethal Candida albicans sepsis“.
Gerald Wirnsberger, Florian Zwolanek, Tomoko Asaoka, Ivona Kozieradzki, Luigi Tortola, Reiner A Wimmer, Anoop Kavirayani, Friedrich Fresser, Gottfried Baier, Wallace Y Langdon, Fumiyo Ikeda, Karl Kuchler & Josef M Penninger. Nature Medicine, July 18, 2016. doi: 10.1038/nm.4134.