DIDS modulates VDAC1 oligomerization to suppress intrinsic apoptosis and attenuates in vitro and in vivo RSV infection.

Human respiratory syncytial virus (RSV) is a major pathogen causing acute lower respiratory tract infections in infants, young children, and elderly people worldwide. Viruses often hijack host cell ion channels to optimize their intracellular environment, positioning ion channel blockers as promising antiviral agents. On the outer mitochondrial membrane, voltage-dependent anion channel protein 1 (VDAC1) plays a crucial role in regulating mitochondrial pathway apoptosis and maintaining cellular homeostasis. This study systematically evaluates the antiviral activity of the VDAC1 inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), both in vitro and in vivo. The results demonstrate that VDAC1 is a key factor in RSV infection, and DIDS significantly inhibits viral replication. Functional intervention experiments show that DIDS effectively blocks RSV-induced VDAC1 oligomerization in the mitochondrial membrane, suppressing mitochondrial apoptosis and disrupting chloride ion (Cl(-)) flux, thereby inhibiting viral replication. Exogenous Cl(-) supplementation reverses these effects, further highlighting the critical role of VDAC1 in the life cycle of RSV. In conclusion, the antiviral effects and mechanistic insights of DIDS reveal that VDAC1 regulates mitochondrial-mediated apoptosis while also modulating anion homeostasis to promote viral replication. These findings provide a potential target and theoretical foundation for the development of novel antiviral strategies targeting mitochondrial ion channels.IMPORTANCEThe study evaluates the antiviral activity of the VDAC1 inhibitor DIDS against respiratory syncytial virus (RSV), a major cause of lower respiratory tract infections worldwide. VDAC1 is identified as a key factor in RSV infection, with DIDS significantly inhibiting viral replication by blocking RSV-induced VDAC1 oligomerization in the mitochondrial membrane, suppressing mitochondrial apoptosis, and disrupting chloride ion flux. These findings establish that VDAC1-mediated regulation of anion homeostasis and subsequent mitochondrial-mediated apoptosis is a critical mechanism promoting RSV replication, providing a novel target for antiviral strategies.