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The igniting spark: signal molecule initiates immune response in fungal infections

(Vienna, 5th December 2014) Fungal infections often lead to life-threatening inflammatory reactions with very high mortality rates. Researchers at the Medical University of Vienna have now discovered a new signal molecule that regulates the development of the body's inflammatory immune response right up to sepsis. The discovery of this "igniter" molecule has tremendous potential for the development of new, anti-fungal medications.

Infections with invasive pathogenic fungi are presenting clinicians worldwide with enormous challenges. These infections claim a lot of lives and cause drug costs running into hundreds of billions. The insidious characteristic of fungal infections, however, means that it is often not the actual fungal pathogen itself that causes death, but rather the affected patient's excessive inflammatory immune response (sepsis). The molecular decryption of the mechanisms that lead to these inflammatory reactions are therefore essential for developing better and more efficient anti-fungal therapies.


The working group led by Karl Kuchler at the Max F. Perutz Laboratories (MFPL) of the University of Vienna and the Medical University of Vienna has now discovered a new signal molecule that plays a major role in controlling the development of life-threatening inflammatory sepsis. This work also forms the basis for a new treatment method for affected patients: by blocking this signal molecule using pharmacological means, there was a massive reduction in inflammation and sepsis with invasive fungal infections in an animal model, allowing the immune system to neutralise the infection. 


"We were able to demonstrate for the first time that this intracellular molecule is involved in the regulation of the inflammatory response in the host. It has long been suspected that this signal molecule must play a role in the immune system, since it occurs in virtually every cell in the immune system," says Kuchler. "We were ourselves astonished that this molecule acts like a relay, and that the inflammatory responses following invasive fungal infections are initiated via this molecule."


In the study, which has been published in the highly respected journal "PloS Pathogens", the authors were able to demonstrate that the signal molecule, a member of the Tec kinases family, regulates the activation of an only recently-discovered multi-protein complex (inflammasome). The inflammasome is one of the most important molecular "switches" in the inflammatory immune response. The scientists were also able to decrypt the entire signalling pathway via which the signal transmitter works. By administering medications that chemically block (inhibit) the kinase, sepsis was reduced dramatically in a mouse model. This means that, for the first time, the high mortality rate associated with invasive fungal infections can be reduced.


"The chemical inhibitor of the signal transmitter is not completely unknown, since it is already being tested for the treatment of malignant diseases in clinical phases and is about to be licensed," explains Florian Zwolanek from the Max F. Perutz Laboratories and the Department of Molecular Genetics at the MedUni Vienna, who is the study's primary author. "The results of the study so far have already been extremely positive. Even we hadn't anticipated how effective this substance would be in infectious diseases too.
These results could make the quest for new and efficient treatments for invasive infectious diseases easier. The discovery could also initiate a paradigm shift in the treatment of microbial infectious diseases. Clinical anti-fungal therapies could, instead of what has been the usual practice previously - i.e. controlling the fungal pathogen itself -, regulate the patient's excessive inflammatory immune response. As a result, the uncontrolled immune response (sepsis) can be greatly delayed or even prevented altogether.


Service: PLoS Pathogens
The non-receptor tyrosine kinase Tec controls assembly and activity of the noncanonical caspase-8 inflammasome, Florian Zwolanek, Michael Riedelberger, Valentina Stolz, Sabrina Jenull ,Fabian Istel, Afitap Derya Köprülü, Wilfried Ellmeier & Karl Kuchler.

 

Max F. Perutz Laboratories (MFPL)
Max F. Perutz Laboratories (MFPL) is a research and training centre run jointly by the University of Vienna and the Medical University of Vienna at the Vienna Biocenter. The MFPL employs around 500 scientists working in, on average, 60 research groups focusing on fundamental research in the field of molecular biology. » mfpl.ac.at