Sara Miranda Sara Miranda Caroline Lassnig Caroline Lassnig Kristina Schmidhofer Kristina Schmidhofer Hrönn Kjartansdottir Hrönn Kjartansdottir Claus Vogl Claus Vogl Simone Tangermann Simone Tangermann Irina Tsymala Irina Tsymala Verena Babl Verena Babl Mathias Müller Mathias Müller Karl Kuchler Karl Kuchler Birgit Strobl Birgit Strobl Nature Portfoliuo 2024 Abstract: 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 (IFN?) 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. PDFDocument eng 2025-01-31T09:18:19.220938Z 2024 Signal Transduction Animals Candida Albicans Immunology TYK2 Kinase Metabolism TYK2 Kinase Genetics Mice Interferon-gamma Metabolism Interferon-gamma Immunology Neutrophils Immunology Neutrophils Metabolism Mice Knockout Mice Inbred C57BL Skin Microbiology Skin Immunology Candidiasis Immunology Candidiasis Microbiology Candidiasis Genetics Female Wound Healing Immunology Wound Healing Genetics Candidiasis Cutaneous Immunology Candidiasis Cutaneous Genetics Candidiasis, Cutaneous Metabolism Candidiasis Cutaneous Microbiology Male 9048120 b application/pdf http://creativecommons.org/licenses/by/4.0/