African swine fever virus enhances viral replication by increasing intracellular reduced glutathione levels, which suppresses stress granule formation

Abstract

African swine fever virus (ASFV) is a DNA virus that has significantly impacted the global swine industry. Currently, there are no effective therapies or vaccines against ASFV. Stress granules (SGs), known for their antiviral properties, are not induced during ASFV infection, even though reactive oxygen species (ROS) are generated. The mechanism by which ASFV regulates SGs formation remains unclear. This study demonstrates that ASFV antagonises SGs formation and increases intracellular levels of reduced glutathione (GSH) levels. The use of the GSH inhibitor BSO and the activator NAC confirmed that the ASFV-induced increase in GSH helps to suppress SGs formation and influences viral replication. Additionally, this study revealed that ASFV enhances GSH by upregulating the antioxidant transcription factor NRF2, as well as factors involved in GSH synthesis and regeneration, such as GCLC, and those related to the ferroptosis pathway, such as SLC7A11. Furthermore, the study uncovered that ASFV manipulates intracellular GSH levels by activating the mitochondrial protein AIFM1. This regulatory mechanism helps the virus inhibit the formation of intracellular SGs, thereby creating an optimal environment for viral replication. These findings provide new insights into the molecular strategies employed by ASFV.