phaidra.vetmeduni.ac.at o:3831 DOI 10.1038/s41467-024-54888-6 Lack of TYK2 signaling enhances host resistance to Candida albicans skin infection 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. eng 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 2025-01-31T09:18:20.250Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Miranda;Sara; FN:Sara Miranda END:VCARD BEGIN:VCARD VERSION:3.0 N:Lassnig;Caroline; FN:Caroline Lassnig X-ORCID:https://orcid.org/0000-0001-7905-3620 END:VCARD BEGIN:VCARD VERSION:3.0 N:Schmidhofer;Kristina; FN:Kristina Schmidhofer END:VCARD BEGIN:VCARD VERSION:3.0 N:Kjartansdottir;Hrönn; FN:Hrönn Kjartansdottir X-ORCID:https://orcid.org/0000-0002-2322-3050 END:VCARD BEGIN:VCARD VERSION:3.0 N:Vogl;Claus; FN:Claus Vogl X-ORCID:https://orcid.org/0000-0002-3996-7863 END:VCARD BEGIN:VCARD VERSION:3.0 N:Tangermann;Simone; FN:Simone Tangermann END:VCARD BEGIN:VCARD VERSION:3.0 N:Tsymala;Irina; FN:Irina Tsymala END:VCARD BEGIN:VCARD VERSION:3.0 N:Babl;Verena; FN:Verena Babl END:VCARD BEGIN:VCARD VERSION:3.0 N:Müller;Mathias; FN:Mathias Müller X-ORCID:https://orcid.org/0000-0002-7879-3552 END:VCARD BEGIN:VCARD VERSION:3.0 N:Kuchler;Karl; FN:Karl Kuchler X-ORCID:https://orcid.org/0000-0003-2719-5955 END:VCARD BEGIN:VCARD VERSION:3.0 N:Strobl;Birgit; FN:Birgit Strobl X-ORCID:https://orcid.org/0000-0001-5716-3212 END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 9048120 https://phaidra.vetmeduni.ac.at/o:3831 https://phaidra.vetmeduni.ac.at/api/object/o:3831/thumbnail LOMv1.0 discipline