Lack of TYK2 Signaling Enhances Host Resistance to Candida albicans Skin Infection

Candida albicans is the most common human fungal pathogen, causing diseases ranging from local to life-threating systemic infections. Tyrosine kinase 2 (TYK2), a crucial mediator in several cytokine signaling pathways, has been associated with protective functions in various microbial infections. However, its specific contribution in the immune response to fungal infections has remained elusive. In this study, we show that mice lacking TYK2 or its enzymatic activity exhibit enhanced resistance to C. albicans skin infections, limiting fungal spread and accelerating wound healing. Impaired TYK2-signaling prompted the formation of a distinctive layer of necrotic neutrophils around the fungal pathogens. Transcriptomic analysis revealed TYK2's pivotal role in regulating interferon-inducible genes in neutrophils, thereby impacting their antifungal capacity during infection. Furthermore, we show that TYK2-dependent interferon-gamma (IFNg) production contributes to fungal dissemination from the skin to the kidneys. Our study uncovers a hitherto unrecognized detrimental role of TYK2 in cutaneous C. albicans infections. Overall design: To better understand the impact of TYK2 on the functionality of skin-infiltrating neutrophils, we performed RNA-sequencing of sorted neutrophils. To obtain sufficient and equal numbers of viable neutrophils, we isolated myeloid cells (CD45+CD3-CD19-NK1.1-) from infected skin at day 1 p.i from WT, Tyk2-/- (full body TYK2 knockout) and Tyk2-K923E (kinase-inactive TYK2) mice. The sorted population consisted of around 80% neutrophils with more than 80% viability.