IκBζ is an essential mediator of immunity to oropharyngeal candidiasis.

Cell host & microbe Pub Date : 2023-10-11 Epub Date: 2023-09-18 DOI:10.1016/j.chom.2023.08.016

Tiffany C Taylor, Bianca M Coleman, Samyuktha P Arunkumar, Ipsita Dey, John T Dillon, Nicole O Ponde, Amanda C Poholek, Daniella M Schwartz, Mandy J McGeachy, Heather R Conti, Sarah L Gaffen

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Abstract

Fungal infections are a global threat; yet, there are no licensed vaccines to any fungal pathogens. Th17 cells mediate immunity to Candida albicans, particularly oropharyngeal candidiasis (OPC), but essential downstream mechanisms remain unclear. In the murine model of OPC, IκBζ (Nfkbiz, a non-canonical NF-κB transcription factor) was upregulated in an interleukin (IL)-17-dependent manner and was essential to prevent candidiasis. Deletion of Nfkbiz rendered mice highly susceptible to OPC. IκBζ was dispensable in hematopoietic cells and acted partially in the suprabasal oral epithelium to control OPC. One prominent IκBζ-dependent gene target was β-defensin 3 (BD3) (Defb3), an essential antimicrobial peptide. Human oral epithelial cells required IκBζ for IL-17-mediated induction of BD2 (DEFB4A, human ortholog of mouse Defb3) through binding to the DEFB4A promoter. Unexpectedly, IκBζ regulated the transcription factor Egr3, which was essential for C. albicans induction of BD2/DEFB4A. Accordingly, IκBζ and Egr3 comprise an antifungal signaling hub mediating mucosal defense against oral candidiasis.

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IκBζ是口咽念珠菌感染免疫的重要介质。

真菌感染是一种全球性威胁；然而，目前还没有针对任何真菌病原体的许可疫苗。Th17细胞介导对白色念珠菌的免疫，特别是口咽念珠菌感染（OPC），但其重要的下游机制尚不清楚。在OPC小鼠模型中，IκBζ（Nfkbiz，一种非经典的NF-κB转录因子）以白细胞介素（IL）-17依赖的方式上调，对预防念珠菌感染至关重要。Nfkbiz的缺失使小鼠对OPC高度敏感。IκBζ在造血细胞中是可有可无的，并部分作用于基底上口腔上皮以控制OPC。一个重要的IκBζ依赖性基因靶点是β-防御素3（BD3）（Defb3），一种重要的抗菌肽。人类口腔上皮细胞需要IκBζ通过与DEFB4A启动子结合来诱导IL-17介导的BD2（DEFB4A，小鼠Defb3的人类直系同源物）。出乎意料的是，IκBζ调节转录因子Egr3，这对白色念珠菌诱导BD2/DEFB4A至关重要。因此，IκBζ和Egr3组成了一个抗真菌信号中枢，介导粘膜对口腔念珠菌感染的防御。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Cell host & microbe

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