The Journal of clinical investigation, 2018-11, Vol.128 (11), p.5163-5177
2018
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Details
- Autor(en) / Beteiligte
- Titel
- Human tryptophanyl-tRNA synthetase is an IFN-γ-inducible entry factor for Enterovirus
- Ist Teil von
- The Journal of clinical investigation, 2018-11, Vol.128 (11), p.5163-5177
- Ort / Verlag
- United States: American Society for Clinical Investigation
- Erscheinungsjahr
- 2018
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Enterovirus A71 (EV-A71) receptors that have been identified to date cannot fully explain the pathogenesis of EV-A71, which is an important global cause of hand, foot, and mouth disease and life-threatening encephalitis. We identified an IFN-γ-inducible EV-A71 cellular entry factor, human tryptophanyl-tRNA synthetase (hWARS), using genome-wide RNAi library screening. The importance of hWARS in mediating virus entry and infectivity was confirmed by virus attachment, in vitro pulldown, antibody/antigen blocking, and CRISPR/Cas9-mediated deletion. Hyperexpression and plasma membrane translocation of hWARS were observed in IFN-γ-treated semipermissive (human neuronal NT2) and cDNA-transfected nonpermissive (mouse fibroblast L929) cells, resulting in their sensitization to EV-A71 infection. Our hWARS-transduced mouse infection model showed pathological changes similar to those seen in patients with severe EV-A71 infection. Expression of hWARS is also required for productive infection by other human enteroviruses, including the clinically important coxsackievirus A16 (CV-A16) and EV-D68. This is the first report to our knowledge on the discovery of an entry factor, hWARS, that can be induced by IFN-γ for EV-A71 infection. Given that we detected high levels of IFN-γ in patients with severe EV-A71 infection, our findings extend the knowledge of the pathogenicity of EV-A71 in relation to entry factor expression upon IFN-γ stimulation and the therapeutic options for treating severe EV-A71-associated complications.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9738eISSN: 1558-8238DOI: 10.1172/JCI99411Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6205371
- Format
- –
- Schlagworte
- Alzheimer's disease, Animals, Antigens, Apoptosis, Biomedical research, Cell Membrane - enzymology, Cell Membrane - genetics, Clonal deletion, CRISPR, Cytokines, Disease Models, Animal, Encephalitis, Enterovirus, Enterovirus A, Human - genetics, Enterovirus A, Human - metabolism, Enterovirus Infections - enzymology, Enterovirus Infections - genetics, Enterovirus Infections - pathology, Enteroviruses, Female, Gene expression, Genomes, Hand-foot-and-mouth disease, Humans, Infections, Infectivity, Interferon-gamma - genetics, Meningitis, Mice, Mice, Inbred BALB C, Neurotrophin 2, Pathogenesis, Pathogenicity, Patients, RNA-mediated interference, Transduction, Genetic, tRNA, Tryptophan-tRNA ligase, Tryptophan-tRNA Ligase - genetics, Tryptophan-tRNA Ligase - metabolism, Virus attachment, Virus Internalization, Viruses, γ-Interferon