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Abstract
Fusobacterium nucleatum (F. nucleatum) is an early pathogenic colonizer in periodontitis, but the host response to infection with this pathogen remains unclear. In this study, we built an F. nucleatum infectious model with human periodontal ligament stem cells (PDLSCs) and showed that F. nucleatum could inhibit proliferation, and facilitate apoptosis, ferroptosis, and inflammatory cytokine production in a dose-dependent manner. The F. nucleatum adhesin FadA acted as a proinflammatory virulence factor and increased the expression of interleukin(IL)-1β, IL-6 and IL-8. Further study showed that FadA could bind with PEBP1 to activate the Raf1-MAPK and IKK-NF-κB signaling pathways. Time-course RNA-sequencing analyses showed the cascade of gene activation process in PDLSCs with increasing durations of F. nucleatum infection. NFκB1 and NFκB2 upregulated after 3 h of F. nucleatum-infection, and the inflammatory-related genes in the NF-κB signaling pathway were serially elevated with time. Using computational drug repositioning analysis, we predicted and validated that two potential drugs (piperlongumine and fisetin) could attenuate the negative effects of F. nucleatum-infection. Collectively, this study unveils the potential pathogenic mechanisms of F. nucleatum and the host inflammatory response at the early stage of F. nucleatum infection.
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1 Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Jinan, China (GRID:grid.27255.37) (ISNI:0000 0004 1761 1174); Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Human Microbiome, School and Hospital of Stomatology, Jinan, China (GRID:grid.27255.37) (ISNI:0000 0004 1761 1174)
2 Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Human Microbiome, School and Hospital of Stomatology, Jinan, China (GRID:grid.27255.37) (ISNI:0000 0004 1761 1174)
3 Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Human Microbiome, School and Hospital of Stomatology, Jinan, China (GRID:grid.27255.37) (ISNI:0000 0004 1761 1174); Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Jinan, China (GRID:grid.27255.37) (ISNI:0000 0004 1761 1174)
4 Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Jinan, China (GRID:grid.27255.37) (ISNI:0000 0004 1761 1174)
5 Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Human Microbiome, School and Hospital of Stomatology, Jinan, China (GRID:grid.27255.37) (ISNI:0000 0004 1761 1174); Shandong University, State key laboratory of microbial technology, Qingdao, China (GRID:grid.27255.37) (ISNI:0000 0004 1761 1174)