title: Human respiratory syncytial virus nucleoprotein and inclusion bodies antagonize the innate immune response mediated by MDA5 and MAVS.
abstract: Currently, the spatial distribution of human respiratory syncytial virus (hRSV) proteins and RNAs in infected cells is still under investigation, with many unanswered questions regarding the interaction of virus-induced structures and the innate immune system. Very few studies of hRSV have used subcellular imaging as a means to explore the changes in localization of retinoic-acid-inducible gene-I (RIG-I)-like receptors or the mitochondrial antiviral signaling (MAVS) protein, in response to the infection and formation of viral structures. In this investigation, we found that both RIG-I and melanoma differentiation-associated gene 5 (MDA5) colocalized with viral genomic RNA and the nucleoprotein (N) as early as 6 h postinfection (hpi). By 12 hpi, MDA5 and MAVS were observed within large viral inclusion bodies (IB). We used a proximity ligation assay (PLA) and determined that the N protein was in close proximity to MDA5 and MAVS in IBs throughout the course of the infection. Similar results were found with the transient coexpression of N and the phosphoprotein (P). Additionally, we demonstrated that the localization of MDA5 and MAVS in IBs inhibited the expression of interferon β mRNA 27-fold following Newcastle disease virus infection. From these data, we concluded that the N likely interacts with MDA5, is in close proximity to MAVS, and localizes these molecules within IBs in order to attenuate the interferon response. To our knowledge, this is the first report of a specific function for hRSV IBs and of the hRSV N protein as a modulator of the innate immune response.
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA.
authors.forename: Aaron W
authors.initials: AW
authors.lastname: Lifland
authors.forename: Jeenah
authors.initials: J
authors.lastname: Jung
authors.forename: Eric
authors.initials: E
authors.lastname: Alonas
authors.forename: Chiara
authors.initials: C
authors.lastname: Zurla
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Santangelo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001717:Birds; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016679:Genome, Viral / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D045586:Intranuclear Inclusion Bodies / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009521:Newcastle Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009522:Newcastle disease virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009698:Nucleoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018113:Respiratory Syncytial Virus, Human / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D009698:Nucleoproteins; D012333:RNA, Messenger; D012367:RNA, Viral; D011971:Receptors, Immunologic; D014764:Viral Proteins; D016899:Interferon-beta; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1