TNFα Impairs Rhabdoviral Clearance by Inhibiting the Host Autophagic Antiviral Response

PLoS Pathogens

Azucena López-Muñoz¹  Sylwia D. Tyrkalska¹  Sergio Candel¹  Victoriano Mulero¹  Diana García-Moreno¹  Raquel Espín-Palazón¹  Francisco J. Roca¹  José Meseguer¹  Amparo Estepa²  Alberto Falco²  Alicia Martínez-López² 

[1] Departamento de Biología Celular e Histología. Facultad de Biología. Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain;Instituto de Biología Celular y Molecular, Universidad Miguel Hernández, Elche, Spain

关键词: Larvae;    Autophagic cell death;    Zebrafish;    Viral replication;    Viral transmission;    infection;    Interferons;    Gene expression;    Antiviral immune response;   

DOI  :  10.1371/journal.ppat.1005699

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY