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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.

Original publication




Journal article


Proc Natl Acad Sci U S A

Publication Date





E3214 - E3223


T lymphocyte priming, cSMAC, nucleocapsid protein, pSMAC, Animals, Brefeldin A, CD4-Positive T-Lymphocytes, Cell Communication, Cell Line, Cell Membrane, Dendritic Cells, Golgi Apparatus, Histocompatibility Antigens, Humans, Immunological Synapses, Lipid Bilayers, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Nucleoproteins, Peptides, Protein Transport, Receptors, Antigen, T-Cell, Respiratory Syncytial Virus Infections, Respiratory Syncytial Virus, Human, Signal Transduction, Viral Proteins, Virus Replication