TNFα 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 TNFα to their benefit. Some recent reports have shown that anti-TNFα therapies could be utilized to treat certain viral infections. However, the underlying mechanisms by which TNFα 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 TNFα in certain viral infections.
Tumor necrosis factor alpha (TNFα) is one of the main pro-inflammatory cytokines produced in response to a broad type of infections [ 1]. Although TNFα has a crucial role in protecting the host organism from pathogens, its deregulation can promote susceptibility to pathogens by impairing pathogen clearance and, ultimately, promoting maintenance of infection and death. In addition, some viruses might utilize the host produced TNFα to their benefit. Thus, anti-TNFα therapies could be utilized to treat certain viral infections. However, the underlying mechanisms by which TNFα can favor certain virus replication have not been identified. Here, we have used a viral infection model in zebrafish to identify the mechanism of action by which TNFα has a deleterious role for the host to combat certain viral infections. Our results demonstrate that Tnfa does not affect viral ability to infect host cells or to antagonize the main host antiviral pathway, namely the interferon pathway. However, Tnfa impairs viral clearance by blocking the host autophagy response, which is usually used by host cells to degrade unnecessary or dysfunctional cellular components, and that we found to be critical to eliminate intracellular viral particles. This mechanism of action provides new therapeutic targets for the treatment of SVCV-infected fish in aquaculture and probably to other viral infection affecting cattle industry and human.