Abstract
Periodontal disease is caused by dental plaque biofilms. Fusobacterium nucleatum is an important periodontal pathogen involved in the development of bacterial complexity in dental plaque biofilms. Human gingival fibroblasts (GFs) act as the first line of defense against oral microorganisms and locally orchestrate immune responses by triggering the production of reactive oxygen species and pro-inflammatory cytokines (IL-6 and IL-8). The frequency and severity of periodontal diseases is known to increase in elderly subjects. However, despite several studies exploring the effects of aging in periodontal disease, the underlying mechanisms through which aging affects the interaction between F. nucleatum and human GFs remain unclear. To identify genes affected by infection, aging, or both, we performed an RNA-Seq analysis using GFs isolated from a single healthy donor that were passaged for a short period of time (P4) ‘young GFs’ or for longer period of time (P22) ‘old GFs’, and infected or not with F. nucleatum. Comparing F. nucleatum-infected and uninfected GF(P4) cells the differentially expressed genes (DEGs) were involved in host defense mechanisms (i.e., immune responses and defense responses), whereas comparing F. nucleatum-infected and uninfected GF(P22) cells the DEGs were involved in cell maintenance (i.e., TGF-β signaling, skeletal development). Most DEGs in F. nucleatum-infected GF(P22) cells were downregulated (85%) and were significantly associated with host defense responses such as inflammatory responses, when compared to the DEGs in F. nucleatum-infected GF(P4) cells. Five genes (GADD45b, KLF10, CSRNP1, ID1, and TM4SF1) were upregulated in response to F. nucleatum infection; however, this effect was only seen in GF(P22) cells. The genes identified here appear to interact with each other in a network associated with free radical scavenging, cell cycle, and cancer; therefore, they could be potential candidates involved in the aged GF’s response to F. nucleatum infection. Further studies are needed to confirm these observations.
Highlights
Periodontitis is one of the most prevalent diseases worldwide and is the major cause of tooth loss in adults
Using RNA-seq technology, this study reports a novel, quantitative, and comprehensive gene expression mapping in gingival fibroblasts (GFs) following F. nucleatum infection, and examines the effect of cell age
We have shown that F. nucleatum infection in GFs triggers reactive oxygen species (ROS) generation, which is involved in the host defense mechanism
Summary
Periodontitis is one of the most prevalent diseases worldwide and is the major cause of tooth loss in adults. Fusobacterium nucleatum is a facultative oral bacterium that mediates aggregations between early (streptococci and actinomycetes) and late colonizers (Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola), which are strongly implicated in the pathogenesis of periodontal disease [2, 3]. It is known that F. nucleatum contributes to the reducing environment necessary for the emergence of oxygen-intolerant anaerobes [4, 5]. We recently reported that F. nucleatum stimulates P. gingivalis growth by triggering the activation of NADPH oxidase in host cells, which could provide a favorable environment for strictly anaerobic bacteria [6]. F. nucleatum adheres to, and invades, human epithelial cells directly and might mediate the entry of non-invasive bacteria
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