1. Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells
- Author
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Alison Creneguy, Catarina Sacristán, Susan M. Bueno, Jorge E. Mora, Michael Cammer, Tuan H. Nguyen, Alexis M. Kalergis, Juan Pablo Mackern-Oberti, David Depoil, Bruno A. Ramirez, Christian E. Palavecino, Michael L. Dustin, Roberto S. Gomez, Claudia A. Riedel, Sebastián A. Riquelme, Pablo F. Céspedes, Departamento de Microbiologıa y Genetica Molecular [Santiago, Chile] (Facultad de Ciencias Biologicas), Pontificia Universidad Católica de Chile (UC), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Helen and Martin Kimmel Center for Biology and Medicine [New York, NY, USA], New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU), Kennedy Institute of Rheumatology [Oxford, UK], Imperial College London, Departamento de Ciencias Biologicas [Santiago, Chile] (Facultad de Ciencias Biologicas y Facultad de Medicina), Universidad Andrés Bello [Santiago] (UNAB), Departamento de Inmunologıa Clınica y Reumatologıa [Santiago, Chile] (Escuela de Medicina), Fondo Nacional de Desarrollo Científico y Tecnológico Grants 3100090, 1070352, and 3140455., Fondo de Fomento al Desarrollo Científico y Tecnológico D061008., Millennium Institute on Immunology and Immunotherapy (P07/088-F)., Grant 'Nouvelles Equipes-nouvelles thématiques' from the La Région Pays De La Loire., Evaluation-Orientation of Scientific Cooperation France-Chile Grant., Comisión Nacional de Investigación Científica y Tecnológica (CONICYT)., A Becas Chile scholarship., Proyecto de Inserción de Capital Humano en la Academia no. 79100015 from CONICYT., National Institutes of Health Grants AI043542 and AI080192., Wellcome Trust and Kennedy Trust., and Le Bihan, Sylvie
- Subjects
CD4-Positive T-Lymphocytes ,Cell signaling ,Immunological Synapses ,Lipid Bilayers ,Receptors, Antigen, T-Cell ,Golgi Apparatus ,chemical and pharmacologic phenomena ,Cell Communication ,Respiratory Syncytial Virus Infections ,Biology ,Lymphocyte Activation ,Virus Replication ,Cell Line ,Immunological synapse ,Mice ,Viral Proteins ,03 medical and health sciences ,Histocompatibility Antigens ,Animals ,Humans ,T lymphocyte priming ,030304 developmental biology ,0303 health sciences ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Brefeldin A ,Multidisciplinary ,Synapse assembly ,Immunological synapse formation ,030306 microbiology ,Cell Membrane ,T-cell receptor ,Dendritic Cells ,Acquired immune system ,Virology ,3. Good health ,Transport protein ,Cell biology ,Mice, Inbred C57BL ,Protein Transport ,Nucleoproteins ,PNAS Plus ,Respiratory Syncytial Virus, Human ,Signal transduction ,Peptides ,pSMAC ,cSMAC ,nucleocapsid protein ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Signal Transduction - Abstract
International audience; 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.
- Published
- 2014