Researchers from the IMBA (Institute of Molecular Biotechnology) and the Max F. Perutz Laboratories (MFPL) at MedUni Vienna and the University of Vienna in Austria have discovered a new mechanism that could lead to a treatment for life-threatening fungal infections.
The scientists have discovered that 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 most common infections worldwide – one in four people will suffer from an infection of the skin or mucous membranes in their lifetime. However, 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. But if our immune system fails to recognise the pathogen, the fungus can spread throughout the body and can lead to fungal sepsis, a dangerous form of blood poisoning. Such 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. 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.
Our research marks the first milestone on the way to a completely new type of treatment for Candida albicans
The Viennese scientists 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 recognised by '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 Kuchler (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 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,' said Professor Kuchler.
