TNFα Impairs Rhabdoviral Clearance by Inhibiting the Host Autophagic Antiviral Response.

TNF alpha is a pleiotropic pro-inflammatory cytokine with a key role in the activation of the immune system to fight viral infections. Despite its antiviral role, a few viruses might utilize the host produced TNF alpha to their benefit. Some recent reports have shown that anti-TNF alpha therapies could be utilized to treat certain viral infections. However, the underlying mechanisms by which TNF alpha can favor virus replication have not been identified. Here, a rhabdoviral infection model in zebrafish allowed us to identify the mechanism of action by which TNF alpha has a deleterious role for the host to combat certain viral infections. Our results demonstrate that TNF alpha signals through its receptor Tnfr2 to enhance viral replication. Mechanistically, TNF alpha does not affect viral adhesion and delivery from endosomes to the cytosol. In addition, the host interferon response was also unaffected by TNF alpha levels. However, TNF alpha blocks the host autophagic response, which is required for viral clearance. This mechanism of action provides new therapeutic targets for the treatment of SVCV-infected fish, and advances our understanding of the previously enigmatic deleterious role of TNF alpha in certain viral infections.