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bioRxiv · 10.1101/2025.08.25.671995

An estrogen-independent and IL-1-dependent pathway controls vulvovaginal candidiasis through combined IL-17/IL-22 signaling

Coleman, B. M.·Cook, M. E.·Khan, M. R.·Vogel, A.·Wells, A.·Miao, J.·Vyas, S.·Taylor, T. C.·Aggor, F.·Ponde, N. O.·Dey, I.·Zou, H.·Peters, B. M.·Gaffen, S.
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Abstract

Vulvovaginal candidiasis (VVC) affects >75% of women, with considerable morbidity and high medical cost burden. While Type 17 cytokines (IL-17, IL-22) are critical for oral and dermal immunity to C. albicans, their role in VVC has been less clear. Th17 gene signatures are potently upregulated in VVC, yet impairment of individual Th17 components (IL-17A, IL-17R subunits, IL-22) does not worsen disease. Rather, estrogen activity is tightly linked to VVC, leading to a paradigm that hormonal pathways rather than immune defense, dominate susceptibility. Here, we reveal a previously unappreciated role for IL-1/Type 17 in VVC that operates independently of estrogenic hormones. In contrast to mice lacking IL-17A, IL-17RA, IL-22, or IL-22R individually, mice lacking IL-17RA and IL-22RA1 together (Il17raIl22ra1-/-) exhibited high fungal loads and exacerbated tissue damage and inflammation. In human vulvar epithelial cells, IL-17 and IL-22 drive synergistic signaling. IL-1R signaling but surprisingly not IL-23 wa upstream of this response. Il17raIl22ra1-/- mice expressed high IL-1{beta} yet did not control disease, indicating that IL-1 is upstream but not downstream of Type 17 responses. Unexpectedly, Type 17-dependent control occurred in the absence of exogenous estrogen administration and persisted even when estrus was prevented by progesterone treatment. Collectively, these data indicate that susceptibility to VVC is driven not only by estrogen sensitization but through combinatorial loss of IL-17 and IL-22. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/671995v2_ufig1.gif" ALT="Figure 1000"> View larger version (52K): org.highwire.dtl.DTLVardef@19946e9org.highwire.dtl.DTLVardef@1feac71org.highwire.dtl.DTLVardef@eb433aorg.highwire.dtl.DTLVardef@18ab622_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Coleman, B. M., Cook, M. E., Khan, M. R., Vogel, A., Wells, A., Miao, J., Vyas, S., Taylor, T. C., Aggor, F., Ponde, N. O., Dey, I., Zou, H., Peters, B. M., Gaffen, S.. 2025-08-28. An estrogen-independent and IL-1-dependent pathway controls vulvovaginal candidiasis through combined IL-17/IL-22 signaling. https://doi.org/10.1101/2025.08.25.671995

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