At mucosal barriers, the virulence of microbial communities reflects the outcome of both dysbiotic and eubiotic interactions with the host, with commensal species mitigating or potentiating the action of pathogens. We examined epithelial responses to the oral pathogen Porphyromonas gingivalis as a monoinfection and in association with a community partner, Streptococcus gordonii. RNA-Seq of oral epithelial cells showed that the Notch signaling pathway, including the downstream effector olfactomedin 4 (OLFM4), was differentially regulated by P. gingivalis alone; however, regulation was overridden by S. gordonii. OLFM4 was required for epithelial cell migratory, proliferative and inflammatory responses to P. gingivalis. Activation of Notch signaling was induced through increased expression of the Notch1 receptor and the Jagged1 (Jag1) agonist. In addition, Jag1 was released in response to P. gingivalis, leading to paracrine activation. Following Jag1-Notch1 engagement, the Notch1 extracellular domain was cleaved by P. gingivalis gingipain proteases. Antagonism by S. gordonii involved inhibition of gingipain activity by secreted hydrogen peroxide. The results establish a novel mechanism by which P. gingivalis modulates epithelial cell function which is dependent on community context. These interrelationships have relevance for innate inflammatory responses and epithelial cell fate decisions in oral health and disease.

在粘膜屏障，微生物群落的毒力反映了与宿主的生态失调和合生相互作用的结果，共生物种减轻或加强了病原体的作用。我们检查了上皮细胞对口腔病原体牙龈卟啉单胞菌的反应，将其作为单一感染并与社区伙伴戈登链球菌相关联。口腔上皮细胞的 RNA-Seq 显示 Notch 信号通路，包括下游效应子嗅调蛋白 4 (OLFM4)，仅受牙龈卟啉单胞菌的差异调节；然而，监管被S. gordonii推翻了。上皮细胞对牙龈卟啉单胞菌的迁移、增殖和炎症反应需要 OLFM4. 通过增加 Notch1 受体和 Jagged1 (Jag1) 激动剂的表达来诱导 Notch 信号的激活。此外，Jag1 响应于P. gingivalis被释放，导致旁分泌激活。在 Jag1-Notch1 结合后，Notch1 胞外结构域被P. gingivalis牙龈蛋白酶切割。S. gordonii的拮抗作用涉及分泌的过氧化氢对牙龈蛋白酶活性的抑制。结果建立了一种新机制，牙龈卟啉单胞菌调节依赖于群落环境的上皮细胞功能。这些相互关系与口腔健康和疾病中的先天炎症反应和上皮细胞命运决定有关。