title: TNFα Impairs Rhabdoviral Clearance by Inhibiting the Host Autophagic Antiviral Response.
abstract: 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.
authors.affiliation: Departamento de Biología Celular e Histología. Facultad de Biología. Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Espín-Palazón
authors.affiliation: Instituto de Biología Celular y Molecular, Universidad Miguel Hernández, Elche, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Martínez-López
authors.affiliation: Departamento de Biología Celular e Histología. Facultad de Biología. Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Roca
authors.affiliation: Departamento de Biología Celular e Histología. Facultad de Biología. Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Azucena
authors.initials: A
authors.lastname: López-Muñoz
authors.affiliation: Departamento de Biología Celular e Histología. Facultad de Biología. Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Sylwia D
authors.initials: SD
authors.lastname: Tyrkalska
authors.affiliation: Departamento de Biología Celular e Histología. Facultad de Biología. Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Candel
authors.affiliation: Departamento de Biología Celular e Histología. Facultad de Biología. Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: García-Moreno
authors.affiliation: Instituto de Biología Celular y Molecular, Universidad Miguel Hernández, Elche, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Falco
authors.affiliation: Departamento de Biología Celular e Histología. Facultad de Biología. Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Meseguer
authors.affiliation: Instituto de Biología Celular y Molecular, Universidad Miguel Hernández, Elche, Spain.
authors.forename: Amparo
authors.initials: A
authors.lastname: Estepa
authors.affiliation: Departamento de Biología Celular e Histología. Facultad de Biología. Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Victoriano
authors.identifier: 0000-0001-9527-0211
authors.initials: V
authors.lastname: Mulero
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology; D015153:Blotting, Western; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006790:Host-Parasite Interactions / Q000276:immunology*; D030781:Organisms, Genetically Modified; D016133:Polymerase Chain Reaction; D012209:Rhabdoviridae / Q000276:immunology; D018353:Rhabdoviridae Infections / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D014779:Virus Replication / Q000502:physiology; D015027:Zebrafish
chemical_list: D014409:Tumor Necrosis Factor-alpha