Date on Master's Thesis/Doctoral Dissertation
Interdisciplinary and Graduate Studies
Interdisciplinary Studies (Individualized Degree), PhD
Committee Co-Chair (if applicable)
P. gingivalis; S. gordonii; OSCC; OLFM4; microbial communities; Notch signaling
Porphyromonas gingivalis, a keystone pathogen for periodontal disease, initiates a complex molecular dialogue with gingival epithelial cells, leading ultimately to disruption of host signaling pathways. Dysbiotic host responses are also thought to contribute to the initiation and progression of oral squamous cell carcinomas. Recently, the homeostatic commensal Streptococcus gordonii has been shown to antagonize P. gingivalis-induced epithelial cell signaling events in host cells, such as proliferation and migration. The aim of this study was to characterize pathways that P. gingivalis targets to disturb host signaling, with a specific focus on pathways that S. gordonii can restore to homeostatic levels in the presence of P. gingivalis. RNAseq analysis of gingival epithelial cells challenged with P. gingivalis revealed a transcriptional pattern reflecting activation of Notch signaling. Signaling is activated by proteolytic cleavage of Notch and Jag1 by gingipain proteases and leads to upregulation of Olfactomedin 4 (OLFM4). This activation is antagonized by S. gordonii through the secretion of hydrogen peroxide, which inactivates the gingipains, preventing proteolytic cleavage of Notch1 and Jag1, ultimately blocking OLFM4 upregulation. OLFM4 is required for P. gingivalis-induced epithelial cell migration. RNAseq analysis identified an OLFM4-independent immune signature that included increased expression of CXCL8, CXCL10, and CXCL11 in epithelial cells transfected with siRNA and then challenged with P. gingivalis. In addition, a tissue culture model revealed that OLFM4 was required for P. gingivalis-induced epithelial cell migration. OLFM4 therefore represents a new axis by which P. gingivalis disturbs homeostasis at the mucosal barrier, as well as an additional mechanism for ameliorating this disruption by S. gordonii. This study provides insight into the complex molecular dialogue at the mucosal-microbe interface, and as a result expands on the need for new therapeutic approaches to prevent and identify those at high-risk for oral squamous cell carcinoma.
Fitzsimonds, Zackary Ray, "Epithelial responses to Porphyromonas gingivalis in the community context." (2020). Electronic Theses and Dissertations. Paper 3508.