title: Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells.
abstract: Human respiratory syncytial virus (hRSV) is the leading cause of bronchiolitis and pneumonia in young children worldwide. The recurrent hRSV outbreaks and reinfections are the cause of a significant public health burden and associate with an inefficient antiviral immunity, even after disease resolution. Although several mouse- and human cell-based studies have shown that hRSV infection prevents naïve T-cell activation by antigen-presenting cells, the mechanism underlying such inhibition remains unknown. Here, we show that the hRSV nucleoprotein (N) could be at least partially responsible for inhibiting T-cell activation during infection by this virus. Early after infection, the N protein was expressed on the surface of epithelial and dendritic cells, after interacting with trans-Golgi and lysosomal compartments. Further, experiments on supported lipid bilayers loaded with peptide-MHC (pMHC) complexes showed that surface-anchored N protein prevented immunological synapse assembly by naive CD4(+) T cells and, to a lesser extent, by antigen-experienced T-cell blasts. Synapse assembly inhibition was in part due to reduced T-cell receptor (TCR) signaling and pMHC clustering at the T-cell-bilayer interface, suggesting that N protein interferes with pMHC-TCR interactions. Moreover, N protein colocalized with the TCR independently of pMHC, consistent with a possible interaction with TCR complex components. Based on these data, we conclude that hRSV N protein expression at the surface of infected cells inhibits T-cell activation. Our study defines this protein as a major virulence factor that contributes to impairing acquired immunity and enhances susceptibility to reinfection by hRSV.
authors: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, and.
authors: Pablo F
authors: PF
authors: Céspedes
authors: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, and.
authors: Susan M
authors: SM
authors: Bueno
authors: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, and.
authors: Bruno A
authors: BA
authors: Ramírez
authors: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, andInstitut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, F44093 Nantes, France;
authors: Roberto S
authors: RS
authors: Gomez
authors: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, andInstitut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, F44093 Nantes, France;
authors: Sebastián A
authors: SA
authors: Riquelme
authors: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, and.
authors: Christian E
authors: CE
authors: Palavecino
authors: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, and.
authors: Juan Pablo
authors: JP
authors: Mackern-Oberti
authors: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, and.
authors: Jorge E
authors: JE
authors: Mora
authors: Helen and Martin Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016;Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxon OX3 7FY, United Kingdom; and.
authors: David
authors: D
authors: Depoil
authors: Helen and Martin Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016;
authors: Catarina
authors: C
authors: Sacristán
authors: Helen and Martin Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016;
authors: Michael
authors: M
authors: Cammer
authors: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, F44093 Nantes, France;
authors: Alison
authors: A
authors: Creneguy
authors: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, F44093 Nantes, France;
authors: Tuan H
authors: TH
authors: Nguyen
authors: Millennium Institute on Immunology and Immunotherapy, Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas y Facultad de Medicina, Universidad Andrés Bello, Santiago 8370146, Chile.
authors: Claudia A
authors: CA
authors: Riedel
authors: Helen and Martin Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016;Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxon OX3 7FY, United Kingdom; and.
authors: Michael L
authors: ML
authors: Dustin
authors: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, andInstitut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, F44093 Nantes, France;Departamento de Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile; akalergis@bio.puc.cl.
authors: Alexis M
authors: AM
authors: Kalergis
mesh_terms: D000818:Animals; D020126:Brefeldin A / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D002450:Cell Communication; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006649:Histocompatibility Antigens / Q000276:immunology; D006801:Humans; D054992:Immunological Synapses / Q000187:drug effects / Q000276:immunology*; D008051:Lipid Bilayers / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009698:Nucleoproteins / Q000378:metabolism*; D010455:Peptides / Q000276:immunology; D021381:Protein Transport / Q000187:drug effects; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014764:Viral Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D006649:Histocompatibility Antigens; D008051:Lipid Bilayers; D009698:Nucleoproteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins; D020126:Brefeldin A
keywords: T lymphocyte priming; cSMAC; nucleocapsid protein; pSMAC