Largemouth bass virus infection subverts immune-redox homeostasis in zebrafish and is associated with coordinated suppression of NF-κB and Nrf2 signaling.
Abstract
From lower vertebrates to higher mammals, oxidative stress and inflammatory responses form a tightly regulated homeostatic network, yet the virus-specific mechanisms that coordinate these processes remain unclear. Here, we investigated this question using Largemouth bass virus (LMBV) in both zebrafish in vivo infection models and ZF4 cell in vitro infection models. In vivo, LMBV successfully infected and replicated in TU-strain zebrafish, causing significant histopathological damage, locomotor impairment, and approximately 40% mortality. Transcriptomic analysis of spleens from infected fish revealed that differentially expressed genes were significantly enriched in pathways related to immune regulation and oxidative stress. To explore the underlying mechanisms, we established an LMBV-ZF4 cell infection model. We found that LMBV orchestrates a dual regulatory strategy by coordinately suppressing the transcription factors NF-κB and Nrf2. On the immune front, LMBV inhibited the phosphorylation of JNK, p38 MAPK, and IκBα, thereby blocking p65 nuclear translocation and downregulating key pro-inflammatory cytokines, ultimately impairing innate immune activation. On the antioxidant front, LMBV disrupted the PI3K/AKT/Nrf2 axis by inhibiting PI3K and AKT phosphorylation, preventing Nrf2 nuclear translocation and diminishing the transcriptional activation of ARE-driven genes. Consequently, antioxidant defenses collapsed, leading to sustained accumulation of virus-induced ROS, which not only facilitated viral immune evasion but also exacerbated oxidative damage to host cellular components. In summary, our study reveals that LMBV co-opts the host immune-redox regulatory axis by coordinately suppressing NF-κB-mediated innate immunity and Nrf2-mediated antioxidant defense. This previously unrecognized dual-suppression mechanism represents a novel strategy that promotes viral infection. These findings enhance our understanding of virus-host interplay and lay a conceptual foundation for the development of novel antiviral therapeutics targeting this host signaling axis.