Reactive oxygen species activate NFκB (p65) and p53 and induce apoptosis in RVFV infected liver cells

This study investigates the cellular mechanisms underlying the severe liver damage frequently associated with Rift Valley fever virus (RVFV) infection. Given the known involvement of host phospho-signaling pathways and reactive oxygen species (ROS) in viral pathogenesis, the researchers hypothesized that RVFV infection induces oxidative stress in liver cells. To test this, they used the attenuated RVFV strain MP-12 to infect HepG2 liver cells and primary hepatocytes. The team employed various experimental techniques, including MitoSox staining for ROS detection, confocal microscopy for protein localization, mass spectrometry for protein interaction mapping, and size-exclusion chromatography to examine changes in signaling complexes like NFkB (p65) and p53. Finally, they assessed whether antioxidant treatment could rescue the cells from virus-induced apoptosis.

The researchers found that RVFV infection rapidly increases intracellular ROS levels in liver cells. This early oxidative burst is specifically tied to the viral nonstructural protein NSs, which was shown to localize to the mitochondria and interact with components of the mitochondrial respiratory machinery. This oxidative stress acts as a critical upstream trigger for the activation of key transcription factors, specifically p65 and p53. Activation of these factors involves a macromolecular reorganization of their complexes, allowing them to bind more efficiently to target promoters, which drives the expression of pro-inflammatory cytokines like IL8 and pro-apoptotic genes like Noxa. Importantly, pretreatment with antioxidants—such as curcumin or quercetin—effectively suppressed this ROS-mediated pathway, leading to decreased inflammatory cytokine levels, diminished p53/p65 activation, and, ultimately, reduced apoptosis of the infected liver cells.

This study provides a clearer picture of how RVFV manipulates host cell biology to cause tissue-specific damage. By linking viral protein localization (NSs in the mitochondria) to specific downstream signaling cascades (ROS-p65/p53), the authors identify potential host-pathogen interaction points that contribute to pathology. These results are significant because they highlight the potential of antioxidant-based therapies to provide hepatoprotection during RVFV infection, potentially mitigating liver damage even if viral replication is not completely halted.