TYK2 Deficiency Found to Protect Against Candida albicans Infections

Candida albicans (C. albicans), the most common human fungal pathogen, causes a wide range of infections, ranging from recurrent oral and genital infections to life-threatening invasive diseases. Researchers at the University of Veterinary Medicine Vienna have made a significant discovery: the absence of Tyrosine Kinase 2 (TYK2), a protein critical for immune signalling, enhances resistance to C. albicans infections. This work was recently published in the Scientific Journal Nature Communications.

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TYK2 is essential for regulating immune responses through its role in cytokine signalling and is crucial for the defence against pathogens. Interestingly, while TYK2-deficient patients are highly susceptible to bacterial and viral infections, they do not have an increased risk of developing fungal infections. Patients with activating TYK2 mutations can develop inflammatory and autoimmune diseases, such as psoriasis. This dual role – both protective and disease-promoting – motivated Birgit Strobl’s team (Centre of Biological Sciences, Vetmeduni) to investigate TYK2’s role in fungal immunity, a topic that had not been studied before.

The research team uncovered a surprising function for TYK2: in contrast to its protective role in the defence against bacterial and viral pathogens, TYK2 impairs the immune response to local fungal infections with Candida albicans.

“We used C. albicans to establish a fungal infection model in mice lacking TYK2 because this fungal pathogen represents a significant health burden, causing millions of infections worldwide each year,” explained the study’s first author Sara Miranda from the Centre of Biological Sciences at Vetmeduni. “We focused on skin infections, as the immune response to localized fungal disease is not as well characterized as that to systemic infections“, she added.

The research was conducted in collaboration with the Karl Kuchler team (Max Perutz Labs, Medical University of Vienna), experts in fungal biology and pathogenesis, within the framework of the FWF-funded doc.fund project TissueHome.

By employing genetically modified mouse models, the researchers showed that the absence of TYK2 activity improves infection control, accelerates wound healing, and significantly reduces fungal spread to other organs, such as the kidneys.

The study also provided insights into how TYK2 affects immune cell behaviour. In TYK2-deficient mice, neutrophils – immune cells that act as first responders – formed a dense, protective barrier of mostly dead cells around the infection site, effectively containing the fungus and preventing its dissemination. TYK2-dependent signals, particularly those driving the production of a protein called interferon-gamma (IFNγ), were found to promote C. albicans invasion into the deep skin and spread to distant organs.

This discovery is particularly relevant given the growing clinical use of TYK2 inhibitors, such as Deucravacitinib, to treat autoimmune diseases like psoriasis. The findings suggest that TYK2 inhibitors do not increase the risk of fungal infections but may even hold promise as therapeutic option for treating invasive fungal diseases.

The article „Lack of TYK2 signaling enhances host resistance to Candida albicans skin infection“ by Sara Miranda et al. was published in Nature Communications.

Scientific article

Scientific contacts:
Dr.rer.nat. Birgit Strobl
Centre of Biological Sciences
University of Veterinary Sciences (Vetmeduni)
Birgit.Strobl@vetmeduni.ac.at

Sara Catarina Da Silva Miranda
Centre of Biological Sciences
University of Veterinary Sciences (Vetmeduni)
SaraCatarina.DaSilvaMiranda@vetmeduni.ac.at

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