Gasdermin E couples mitochondrial stress to STING-driven neuronal pyroptosis during Chandipura virus encephalitis

Abstract

Neurotropic RNA viruses are major causes of fatal encephalitis worldwide, yet how infected neurons transition from antiviral defense to inflammatory cell death is not well characterized. Chandipura virus (CHPV), an emerging neurotropic rhabdovirus, causes acute, rapidly progressive encephalitis with high case fatality in children, but the mechanisms underlying its neuropathogenesis remain poorly defined. Here, we demonstrate that CHPV suppresses canonical RNA virus sensing early but subsequently switches to a mitochondria-driven innate immune program that culminates in inflammatory cell death. Early infection of neuronal cells with CHPV was marked by reduced levels of the mitochondrial antiviral adaptor protein, MAVS and attenuation of type I and III interferon responses. As infection progressed, mitochondrial dysfunction promoted accumulation of mtROS, mitochondrial accumulation of cleaved GSDME and cytosolic mtDNA release, triggering STING activation, which coincided with robust neuroinflammation and pyroptotic cell death. Pharmacological inhibition or genetic silencing of STING markedly attenuated inflammatory signaling, prevented pyroptotic membrane rupture and protected neurons from cell death without significantly affecting viral replication. In contrast, GSDME depletion reduced both viral replication and neuronal death. Notably, GSDME depletion markedly attenuated STING phosphorylation, while STING depletion also reduced GSDME activation, revealing functional coupling between these pathways during CHPV-induced neuronal injury. Collectively, our findings identify a mitochondria-GSDME-STING axis linking early immune evasion to neuroinflammation during CHPV infection, revealing a previously unrecognized mechanism of inflammatory neuronal death in viral encephalitis and highlighting STING as a potential therapeutic target in certain CNS viral infections.