TNF[alpha] 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 Tnfa has a deleterious role for the host to combat certain viral infections. Our results demonstrate that Tnfa signals through its receptor Tnfr2 to enhance viral replication. Mechanistically, Tnfa does not affect viral adhesion and delivery from endosomes to the cytosol. In addition, the host interferon response was also unaffected by Tnfa levels. However, Tnfa 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.