Inducing the Localization of HSP70 to Lipid Rafts by Borna Disease Virus 1 Promotes Its Invasion and Host Cells Apoptosis

Abstract

Abstract The Borna disease virus 1 (BoDV-1) is an emerging zoonotic virus causing severe and mostly fatal encephalitis in humans. Increasing evidence of human infections by BoDV-1 has highlighted the importance of antiviral drugs against BoDV-1. However, the process of BoDV-1 infection and its pathogenic mechanism remain elusive and there are few drugs targeting BoDV-1 infection. Our previous research suggests that BoDV-1 infects cells through lipid-related pathways. Heat shock protein 70 (HSP70) in lipid rafts (LR) has been identified to participate in various viral infections. In this study, we reported that the LR-HSP70-Caspase-3 axis engages BoDV-1 invasion and host cell apoptosis. Mechanistically, the LR inhibitor, Methyl-β-cyclodextrin (MβCD), interferes the localization HSP70 to LR and prevents BoDV-1 entry without reducing cell viability.Furthermore, we confirmed that the HSP70 is recruited into LR after BoDV-1 invasion by HSP70 knockdown and overexpression assays. And the migration of HSP70 to LR weakened the interaction between HSP70 and Caspase-3, which reducing the chaperone protective ability of HSP70 to Caspase-3, increasing the intracellular active Caspase-3 and promoting host cell apoptosis. Importantly, the MβCD treatment can effectively alleviate the symptoms and pathological changes in a model of BoDV-1 encephalitis, suggesting a significant antiviral effect in vivo. Our report reveals the process of BoDV-1 invasion and the mechanisms by which MβCD inhibits the infection, offering potential guidance for the development in the targeted treatment of BoDV-1 infection.