Abstract
Fusobacterium nucleatum (F. nucleatum) is a crucial periodontal pathogen and human gingival fibroblasts (GFs) are the first line of defense against oral pathogens. However, the research on potential molecular mechanisms of host defense and effective treatment of F. nucleatum infection in GFs remains scarce. In this study, we undertook a time-series experiment and performed an RNA-seq analysis to explore gene expression profiles during the process of F. nucleatum infection in GFs. Differentially expressed genes (DEGs) could be divided into three coexpression clusters. Functional analysis revealed that the immune-related signaling pathways were more overrepresented at the early stage, while metabolic pathways were mainly enriched at the late stage. We computationally identified several U.S. Food and Drug Administration (FDA)-approved drugs that could protect the F. nucleatum infected GFs via a coexpression-based drug repositioning approach. Biologically, we confirmed that six drugs (etravirine, zalcitabine, wortmannin, calcium D-pantothenate, ellipticine, and tanespimycin) could significantly decrease F. nucleatum-induced reactive oxygen species (ROS) generation and block the Protein Kinase B (PKB/AKT)/mitogen-activated protein kinase signaling pathways. Our study provides more detailed molecular mechanisms of the process by which F. nucleatum infects GFs and illustrates the value of the cogena-based drug repositioning method and the potential therapeutic application of these tested drugs in the treatment of F. nucleatum infection.
Highlights
Periodontal disease is caused by the interaction of dental plaque biofilm and the host immune system (Sanz et al, 2017)
The results demonstrated that the tested drugs played relevant roles in defending against F. nucleatum infection and protecting gingival fibroblasts (GFs) via F. nucleatum-activated AKT, nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) signaling pathways
The previous transcriptome analysis on F. nucleatum to GFs was a crosssectional study on a single time point of F. nucleatum-treated and untreated oral cells, which is difficult to determine the cytological changes during the invasion of pathogenic bacteria because the pathogenic process is a dynamic process of persistent interaction between the host and pathogens
Summary
Periodontal disease is caused by the interaction of dental plaque biofilm and the host immune system (Sanz et al, 2017). Fusobacterium nucleatum (F. nucleatum) has been confirmed as a highfrequency pathogen in periodontal disease (Moore and Moore, 1994). F. nucleatum could transfer critical periodontal pathogens, such as Porphyromonas gingivalis to periodontal infectious sites, recruit and activate local immune cells, and result in tooth. It has been confirmed that F. nucleatum could invade the tissue and play critical roles in the process of tumorigenesis and metastasis (Kostic et al, 2013; Rubinstein et al, 2013; Bullman et al, 2017; Yang et al, 2017). The pathogenic effect of F. nucleatum on oral cells has rarely been reported
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