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<p>Microbes frequently exist as biofilm-embedded multi-species communities where their interactions may establish or exacerbate chronic infection. Recently, fungi and bacteria have been associated with various human tumor microenvironments, suggesting that dynamic cross-kingdom interactions may directly or indirectly contribute to tumor-associated processes. Here, we aimed to investigate whether cell-free supernatants from mono- and dual-species biofilms of the commonly associated fungus <i>Candida albicans</i> and bacterium <i>Staphylococcus aureus</i> could alter human monocyte responses that promote a tumor-related genetic signature in dysplastic oral epithelial (DOK) cells. Treatment of THP-1 monocytes with <i>S. aureus</i> cell-free supernatant increased the production of proinflammatory cytokines (IL-8, IL-1β, and TNF) and CD86 expression. However, exposure to cell-free supernatants from dual-species biofilm suppressed these responses. To determine the fungal virulence factors responsible, <i>C. albicans</i> mutants deleted for genes involved in adhesion (<i>als3</i>Δ/Δ), hyphal growth (<i>efg1</i>Δ/Δ <i>cph1</i>Δ/Δ), or candidalysin production (<i>ece1</i>Δ/Δ) were assessed during co-culture. While candidalysin was dispensable, loss of hyphal growth or the adhesin Als3p phenocopied effects of <i>S. aureus</i> mono-culture treatment. Conditioned medium from THP-1 cells initially challenged with mono- or dual-biofilm cell-free supernatants was applied to DOK cells to assess <i>TP53</i> and <i>BCL2</i> gene expression. Conditioned medium from <i>S. aureus</i> treated THP-1 cells led to decreased epithelial <i>TP53</i>, but increased <i>BCL2</i> expression, which was reversed by the presence of wild-type <i>C. albicans</i>. These phenotypes were similarly dependent on <i>C. albicans</i> hyphal growth during dual-biofilm co-culture. Collectively, our results reveal that fungal–bacterial interactions may shape the monocyte–epithelial axis by orchestrating immune responses that enhance tumor-associated gene expression in dysplastic oral epithelial cells.</p>

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Candida albicans hyphae modulate Staphylococcus aureus cell-free supernatant during dual biofilm growth to drive molecular signatures of oral dysplasia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月19日

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  • Freddy H. Marin-Dett,
  • Mateus P. Grejo,
  • Valéria Valente,
  • Mariana P. Palaçon,
  • Andreia Bufalino,
  • Brian M. Peters,
  • Paula A. Barbugli

摘要

Microbes frequently exist as biofilm-embedded multi-species communities where their interactions may establish or exacerbate chronic infection. Recently, fungi and bacteria have been associated with various human tumor microenvironments, suggesting that dynamic cross-kingdom interactions may directly or indirectly contribute to tumor-associated processes. Here, we aimed to investigate whether cell-free supernatants from mono- and dual-species biofilms of the commonly associated fungus Candida albicans and bacterium Staphylococcus aureus could alter human monocyte responses that promote a tumor-related genetic signature in dysplastic oral epithelial (DOK) cells. Treatment of THP-1 monocytes with S. aureus cell-free supernatant increased the production of proinflammatory cytokines (IL-8, IL-1β, and TNF) and CD86 expression. However, exposure to cell-free supernatants from dual-species biofilm suppressed these responses. To determine the fungal virulence factors responsible, C. albicans mutants deleted for genes involved in adhesion (als3Δ/Δ), hyphal growth (efg1Δ/Δ cph1Δ/Δ), or candidalysin production (ece1Δ/Δ) were assessed during co-culture. While candidalysin was dispensable, loss of hyphal growth or the adhesin Als3p phenocopied effects of S. aureus mono-culture treatment. Conditioned medium from THP-1 cells initially challenged with mono- or dual-biofilm cell-free supernatants was applied to DOK cells to assess TP53 and BCL2 gene expression. Conditioned medium from S. aureus treated THP-1 cells led to decreased epithelial TP53, but increased BCL2 expression, which was reversed by the presence of wild-type C. albicans. These phenotypes were similarly dependent on C. albicans hyphal growth during dual-biofilm co-culture. Collectively, our results reveal that fungal–bacterial interactions may shape the monocyte–epithelial axis by orchestrating immune responses that enhance tumor-associated gene expression in dysplastic oral epithelial cells.