IkBz is an essential mediator of immunity to oropharyngeal candidiasis

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, IkBz (Nfkbiz, a non-canonical NF-kB 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. IkBz was dispensable in hematopoietic cells and acted partially in the suprabasal oral epithelium to control OPC. One prominent IkBz-dependent gene target was b-defensin 3 (BD3) (Defb3), an essential antimicrobial peptide. Human oral epithelial cells required IkBz for IL-17-mediated induction of BD2 (DEFB4A, human ortholog of mouse Defb3) through binding to the DEFB4A promoter. Unexpectedly, IkBz regulated the transcription factor Egr3, which was essential for C. albicans induction of BD2/DEFB4A. Accordingly, IkBz and Egr3 comprise an antifungal signaling hub mediating mucosal defense against oral candidiasis.