EBV promotes alveolar trabecula resorption via extracellular vesicle remodeling by group IIA secreted phospholipase A2

Epstein-Barr virus (EBV) is an enveloped, double-stranded DNA virus that selectively infects primates. Periodontitis, a common inflammatory disease characterized by alveolar bone destruction, affects more than half of the global adult population. While EBV has been linked to periodontitis due to its pro-inflammatory effects and presence in the human periodontium, its effects on bone metabolism, particularly alveolar bone resorption, remain unclear. This study demonstrated that EBV infection in humanized mice induced osteoclast differentiation and alveolar bone resorption, resulting in sparse trabecular bone patterns and increased lacunae resorption. Extracellular vesicles (EVs) from EBV-infected cells contained M-CSF, essential for osteoclast differentiation, and increased CTSK and RANKL expression in osteoclast precursor cells after uptake. EBV infection increased the expression of group IIA-secreted phospholipase A₂ (sPLA₂-IIA), which hydrolyzed EV membranes to produce lipid mediators such as lysophosphatidic acid (LPA) and arachidonic acid derivatives-both of which induce osteoclast differentiation. Treatment with the sPLA₂ inhibitor varespladib reduced CTSK and RANKL expression in vitro and in vivo, confirming the role of sPLA₂-IIA in osteoclastogenesis. Furthermore, sPLA₂-IIA expression and metabolites were significantly elevated in EVs from the gingival crevicular fluid of EBV-positive patients with periodontitis. These findings suggest that sPLA₂-IIA-mediated hydrolysis of EVs from EBV-infected cells contributes to alveolar bone loss, offering insights intotherapeutic strategies targeting EBV and sPLA₂-IIA to prevent periodontitis progression.