title: Simultaneous neutralization and innate immune detection of a replicating virus by TRIM21.
abstract: Tripartite motif-containing 21 (TRIM21) is a cytosolic immunoglobulin receptor that mediates antibody-dependent intracellular neutralization (ADIN). Here we show that TRIM21 potently inhibits the spreading infection of a replicating cytopathic virus and activates innate immunity. We used a quantitative PCR (qPCR)-based assay to measure in vitro replication of mouse adenovirus type 1 (MAV-1), a virus that causes dose-dependent hemorrhagic encephalitis in mice. Using this assay, we show that genetic ablation of TRIM21 or chemical inhibition of either the AAA ATPase p97/valosin-containing protein (VCP) or the proteasome results in a >1,000-fold increase in the relative level of infection in the presence of immune serum. Moreover, the TRIM21-mediated ability of antisera to block replication was a consistent feature of the humoral immune response in immunized mice. In the presence of immune sera and upon infection, TRIM21 also activates a proinflammatory response, resulting in secretion of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). These results demonstrate that TRIM21 provides a potent block to spreading infection and induces an antiviral state.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors.forename: R E
authors.initials: RE
authors.lastname: Watkinson
authors.forename: J C H
authors.initials: JC
authors.lastname: Tam
authors.forename: M J
authors.initials: MJ
authors.lastname: Vaysburd
authors.forename: L C
authors.initials: LC
authors.lastname: James
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D000257:Adenoviridae Infections / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D018797:Cell Cycle Proteins / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D018792:Encephalitis, Viral / Q000276:immunology*; D005347:Fibroblasts; D007113:Immunity, Innate / Q000276:immunology*; D015848:Interleukin-5 / Q000276:immunology; D017921:Mastadenovirus / Q000276:immunology*; D051379:Mice; D009500:Neutralization Tests; D016133:Polymerase Chain Reaction; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D000074405:Valosin Containing Protein; D014779:Virus Replication / Q000502:physiology; D000099207:SS-A Antigen
chemical_list: D000251:Adenosine Triphosphatases; D057134:Antibodies, Neutralizing; D018797:Cell Cycle Proteins; D017931:DNA Primers; D015848:Interleukin-5; D046988:Proteasome Endopeptidase Complex; D012261:Ribonucleoproteins; D014409:Tumor Necrosis Factor-alpha; D000074405:Valosin Containing Protein; D000099207:SS-A Antigen; C000614179:Vcp protein, mouse