Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells.

Journal article

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: Céspedes, P; Bueno, S; Ramírez, B; Gomez, R; Riquelme, SA

• Publication status: Published
• Publisher: National Academy of Sciences
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Volume: 111
• Issue: 31
• Pages: E3214-E3223
• Publication date: 2014-08-01
• DOI: 10.1073/pnas.1400760111
• EISSN: 1091-6490
• ISSN: 0027-8424
• Language: English
• Keywords: Nucleoproteins; Mice; Virus Replication; Receptors, Antigen, T-Cell; Respiratory Syncytial Virus Infections; Lymphocyte Activation; Immunological Synapses; Animals; Respiratory Syncytial Virus, Human; Cell Line; Viral Proteins; Histocompatibility Antigens; Brefeldin A; Cell Communication; Peptides; Golgi Apparatus; Cell Membrane; Humans; Protein Transport; Dendritic Cells; CD4-Positive T-Lymphocytes; Mice, Inbred C57BL; Lipid Bilayers; Signal Transduction