Infections caused by fungal pathogens, often referred to as hidden killers, take an alarming number of lives every year. Among them, Candida albicans (C. albicans) stands out as the leading pathogen, causing diseases ranging from mild skin infections to life-threatening systemic conditions. In our study “Lack of TYK2 Signaling Enhances Host Resistance to Candida albicans Skin Infection” we revealed that Tyrosine Kinase 2 (TYK2), a key player in the immune defense against bacteria and viruses, surprisingly increases susceptibility to C. albicans skin infections.

At the Birgit Strobl Lab, University of Veterinary Medicine Vienna, we investigate how signaling networks regulate immune responses to various pathogens. Our research focuses on the JAK-STAT pathway, which is utilized by many cytokines to orchestrate the host defense against infections.

 TYK2, a Janus kinase (JAK) protein, is essential for the immune defense against bacterial and viral infections. This becomes evident in patients with TYK2 deficiency, who face heightened susceptibility to these pathogens. In our lab, we use TYK2-deficient mouse models to study TYK2’s role in immunity, as they replicate key features of immune dysregulation seen in patients.

However, TYK2 is a double-edged sword. Cytokine signaling through TYK2 can drive autoimmune and inflammatory diseases, making it a therapeutic target to treat such diseases. TYK2 inhibitors are under investigation in numerous clinical trials, with Deucravacitinib being the first approved TYK2-inhibitor for the treatment of psoriasis.

 Motivated by this duality and having the possibility to join forces with the Karl Kuchler Lab (Max Perutz Labs, Medical University of Vienna), who are experts in fungal biology and pathogenesis, we decided to explore TYK2's role in the immune defense against fungal infections – a topic never studied before.

Fungal infections, though often overlooked, impose a significant health burden. C. albicans, the most common human fungal pathogen, causes systemic infections with a high mortality rate of ~40%. While systemic infections are widely studied due to their severity, local infections are far more common yet less explored. To address this gap, we established a mouse model of C. albicans skin infection, aiming to better understand the immune response to these frequent but underexplored infection route.

We found that the absence of TYK2 in mice enhances the resistance to C. albicans skin infection, indicating that, in contrast to TYK2’s protective role during viral and bacterial infections, it impairs the immune response to fungal infections.

TYK2-deficient mice exhibited better infection control, faster wound healing, and reduced fungal spread compared to wild-type animals. In the absence of TYK2, neutrophils, the first responders to fungal infections, formed a protective barrier around C. albicans, effectively containing the pathogen. Interestingly, this layer was primarily composed of dead neutrophils, suggesting that even nonviable neutrophils can contribute to antifungal defense by forming a protective physical barrier.

 Our findings are particularly important given the increasing clinical use of TYK2 inhibitors for the treatment of autoimmune and inflammatory diseases. They suggest that these inhibitors do not raise the risk of developing C. albicans infections and might even offer a therapeutic option for treating invasive cutaneous candidiasis - a possibility we aim to explore further.

 You can read the full story here and learn more about our lab here. Feel free to reach out with any questions or thoughts!

 Cover drawing and graphical illustration by Sara Miranda.