Unveiling the Etiopathogenic Role of Epstein-Barr Virus in Periodontitis

Abstract

Periodontitis, a prevalent and costly oral disease, remains incompletely understood in its etiopathogenesis. The conventional model attributes it to pathogenic bacteria, but emerging evidence suggests dysbiosis involving bacteria, herpesviruses, and an exaggerated host immune response. Among herpesviruses, Epstein-Barr virus (EBV) closely links to severe periodontitis, yet the mechanisms underlying EBV-related pathogenesis remain elusive. This study examined the presence, methylation patterns, and infection states of EBV in gingival tissues from healthy patients and those with periodontitis. It also assessed gene expression differences associated with EBV through whole-genome transcriptomic profiling in healthy and periodontitis-affected tissues. EBV DNA was found at similar frequencies in healthy and periodontitis tissues, suggesting common EBV infection even before disease manifestation. In healthy tissues, mostly unmethylated EBV genomes indicated lytic infection in gums, consistent with the literature on lytic EBV spread in epithelia and continual significant virus release in the saliva of healthy carriers. Conversely, EBV DNA in periodontitis tissues showed both methylated and unmethylated patterns, suggesting a mix of latent and lytic genomes. This indicates the coexistence of latent EBV in B-cells and lytic EBV in plasma cells (PCs), linking EBV presence with both cell types in periodontitis. Whole-genome transcriptomic analysis revealed distinct expression profiles in EBV-positive periodontitis tissues, with upregulated genes associated with inflammatory/immune responses and B-cell and PC markers, while downregulated genes were related to epithelial structure and organization. The EBV-positive periodontitis signature differed distinctly from that of EBV-positive healthy gums, eliciting only a typical viral-induced immune response. These findings provide new insights into EBV physiopathology in the gum, notably assigning a direct etiopathogenetic contribution to EBV in periodontitis. The results suggest a model where EBV can commonly, and apparently asymptomatically, spread in healthy gingiva but may also aggravate inflammation in the context of gum dysbiosis, involving infiltration of B-cells and PCs and loss of epithelial integrity.