EBV-driven rewiring of Drp1-Mediated mitophagy exacerbates trichloroethylene-induced hypersensitivity syndrome.

The environmental pollutant trichloroethylene (TCE) can induce T-cell-mediated hypersensitivity syndrome. Clinical evidence closely links Epstein-Barr virus (EBV) reactivation to aggravated disease severity, yet the mechanism underlying this chemical-viral synergy remains unknown. Based on the view that hypersensitivity essentially involves sustained activation of effector T-cells and disruption of immune homeostasis, this study aims to investigate how EBV reactivation cooperates with TCE metabolite trichloroethanol (TCOH) to regulate the T-cell apoptosis process by affecting mitochondrial dynamics and autophagy, thereby exacerbating trichloroethylene-induced hypersensitive syndrome (TIHS). Results show that TCOH exposure induces mitochondrial damage and apoptosis in T-cells. However, co-exposure with EBV significantly alleviates TCOH-induced mitochondrial damage by enhancing Drp1-mediated mitochondrial fission and promoting subsequent PINK1/Parkin pathway-dependent mitophagy, which in turn suppresses T-cell apoptosis. In an animal model, administration of the Drp1 inhibitor Mdivi-1 inhibited mitophagy, increased T-cell apoptosis, and effectively alleviated skin and hepatic immune injury in TCE-sensitized mice. This confirms that Drp1 is a key molecular target regulating the T-cell apoptosis program and influencing the progression of TIHS. The study reveals that during TIHS development, EBV reactivation exploits Drp1 to promote mitochondrial fission and mitophagy, thereby hindering the normal apoptotic clearance of activated effector T-cells, leading to their sustained activation and immune attack, which exacerbates tissue inflammation and injury. This finding provides a new scientific perspective for understanding the mechanism by which viral co-exposure aggravates TIHS.