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缺乏酪氨酸激酶2（TYK2）信号传导会增强宿主对白色念珠菌皮肤感染的抵抗力。

Lack of TYK2 signaling enhances host resistance to Candida albicans skin infection.

作者信息

Miranda Sara, Lassnig Caroline, Schmidhofer Kristina, Kjartansdottir Hrönn, Vogl Claus, Tangermann Simone, Tsymala Irina, Babl Verena, Müller Mathias, Kuchler Karl, Strobl Birgit

机构信息

Centre of Biological Sciences, University of Veterinary Medicine Vienna, Vienna, Austria.

Vetbiomodels, University of Veterinary Medicine Vienna, Vienna, Austria.

出版信息

Nat Commun. 2024 Dec 3;15(1):10493. doi: 10.1038/s41467-024-54888-6.

DOI:10.1038/s41467-024-54888-6
PMID:39622833
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11612186/
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 (IFNγ) 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.

摘要

白色念珠菌是最常见的人类真菌病原体，可引发从局部感染到危及生命的全身感染等多种疾病。酪氨酸激酶2（TYK2）是几种细胞因子信号通路中的关键介质，已被证明在各种微生物感染中具有保护作用。然而，其在真菌感染免疫反应中的具体作用仍不明确。在本研究中，我们发现缺乏TYK2或其酶活性的小鼠对白色念珠菌皮肤感染具有更强的抵抗力，可限制真菌扩散并加速伤口愈合。TYK2信号受损促使在真菌病原体周围形成一层独特的坏死中性粒细胞层。转录组分析揭示了TYK2在调节中性粒细胞中干扰素诱导基因方面的关键作用，从而影响其在感染期间的抗真菌能力。此外，我们还表明，TYK2依赖的干扰素-γ（IFNγ）产生有助于真菌从皮肤扩散到肾脏。我们的研究揭示了TYK2在皮肤白色念珠菌感染中迄今未被认识到的有害作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e24/11612186/5c5fd2cd7a21/41467_2024_54888_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e24/11612186/924c162ad41a/41467_2024_54888_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e24/11612186/5c5fd2cd7a21/41467_2024_54888_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e24/11612186/de439c45efc6/41467_2024_54888_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e24/11612186/c3277493f2e0/41467_2024_54888_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e24/11612186/27c905ba12e3/41467_2024_54888_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e24/11612186/c8e2b0390725/41467_2024_54888_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e24/11612186/924c162ad41a/41467_2024_54888_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e24/11612186/5c5fd2cd7a21/41467_2024_54888_Fig8_HTML.jpg

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