Cadmium reprograms type-I interferon signaling to promote Japanese encephalitis virus infection in neuronal cells.

Japanese encephalitis virus (JEV) is a major cause of viral encephalitis and is associated with severe neuroinflammation and neurological damage. Despite extensive research on viral and host determinants of JEV pathogenesis, the influence of environmental factors on disease outcomes remains largely unexplored. This study investigated the impact of Cadmium (Cd), a ubiquitous and persistent environmental heavy metal exposure on JEV infection using in vitro and ex vivo approaches. The findings demonstrate that Cd pre-exposure markedly enhances viral infection, whereas co-exposure and post-exposure have minimal effects on viral infection. Mechanistically, Cd pre-exposure significantly suppressed key virus induced components of the innate antiviral response. Specifically, reduced activation of RIG-I led to the downregulation of TBK1 phosphorylation, which subsequently impaired IRF3 phosphorylation. This attenuation further resulted in decreased expression of STAT1 and STAT2, indicating disruption of downstream interferon signaling. Consistently, the expression of antiviral and inflammatory mediators, including TNF-α, IRF9, and ISG15, was markedly reduced. In contrast, ATF3, a known negative regulator of immune signaling, was significantly upregulated, suggesting its potential involvement in Cd-mediated suppression of antiviral immunity. Together, these results indicate that Cd does not directly enhance viral infection, but instead conditions host cells into an immunologically permissive state prior to infection. This toxicant-induced impairment of innate immunity creates a cellular environment that favours viral establishment and propagation. This study identifies environmental Cd exposure as an important modulator of antiviral immunity and provides insight into how toxicant-induced immune dysregulation can influence viral pathogenesis.