6533b828fe1ef96bd1288692

RESEARCH PRODUCT

ISG15 Is Upregulated in Respiratory Syncytial Virus Infection and Reduces Virus Growth through Protein ISGylation

Rubén González-sanzJesus F. Bermejo-martinManuel De La MataManuel De La MataAmparo ÁLvarezJosé A. MeleroJulio CortijoJulio CortijoIsidoro Martínez

subject

0301 basic medicineSmall interfering RNAvirusesImmunologyCellular Response to InfectionRespiratory Syncytial Virus InfectionsUbiquitin-Activating EnzymesBiologyMicrobiologyVirus03 medical and health sciencesIn vivoImmunityRNA interferenceVirologyCell Line TumorEndopeptidasesHumansRNA Small InterferingRespiratory Tract InfectionsUbiquitinsInnate immune system030102 biochemistry & molecular biologyRespiratory tract infectionsInfantEpithelial CellsISG15VirologyImmunity Innate030104 developmental biologyInsect ScienceRespiratory Syncytial Virus HumanCytokinesRNA InterferenceUbiquitin ThiolesteraseProtein Processing Post-TranslationalHeLa Cells

description

ABSTRACT Human respiratory syncytial virus (RSV), for which neither a vaccine nor an effective therapeutic treatment is currently available, is the leading cause of severe lower respiratory tract infections in children. Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like protein that is highly increased during viral infections and has been reported to have an antiviral or a proviral activity, depending on the virus. Previous studies from our laboratory demonstrated strong ISG15 upregulation during RSV infection in vitro . In this study, an in-depth analysis of the role of ISG15 in RSV infection is presented. ISG15 overexpression and small interfering RNA (siRNA)-silencing experiments, along with ISG15 knockout (ISG15 −/− ) cells, revealed an anti-RSV effect of the molecule. Conjugation inhibition assays demonstrated that ISG15 exerts its antiviral activity via protein ISGylation. This antiviral activity requires high levels of ISG15 to be present in the cells before RSV infection. Finally, ISG15 is also upregulated in human respiratory pseudostratified epithelia and in nasopharyngeal washes from infants infected with RSV, pointing to a possible antiviral role of the molecule in vivo . These results advance our understanding of the innate immune response elicited by RSV and open new possibilities to control infections by the virus. IMPORTANCE At present, no vaccine or effective treatment for human respiratory syncytial virus (RSV) is available. This study shows that interferon-stimulated gene 15 (ISG15) lowers RSV growth through protein ISGylation. In addition, ISG15 accumulation highly correlates with the RSV load in nasopharyngeal washes from children, indicating that ISG15 may also have an antiviral role in vivo . These results improve our understanding of the innate immune response to RSV and identify ISG15 as a potential target for virus control.

yearjournalcountryeditionlanguage
2016-01-13
10.1128/jvi.02695-15http://hdl.handle.net/20.500.12105/8597