Alexis M. Kalergis

Wednesday, 10 January 2018 | 3:00 pm

Millennium Institute Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, CHILE 

Interference with the immunological and neurological synapses as virulence mechanisms of RSV. Implications for vaccine design

(Host: M. Giacca)

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 significant public health burden and associate with an inefficient viral immunity, even after disease resolution. Furthermore, hRSV can also cause severe symptoms, such as dyspnea and chest wall retractions.Recently, neurological symptoms have also been associated withhRSV- respiratory infection and include seizures, central apnea,lethargy, feeding or swallowing difficulties, abnormalities in muscletone, strabismus, abnormalities in the CSF and encephalopathy. 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.

We have shown that the hRSV nucleoprotein (N) could be at least partially responsible of inhibiting T cell activation duringinfection by this virus. Early after infection, the N protein is expressed on the surface of epithelial and dendritic cells, after interacting withtrans-Golgi and lysosomal compartments. Further, experimentson supported lipid bilayers loaded with peptide-MHC complexes,showed that surface-anchored N protein prevented immunological synapse assembly by naive CD4+ T cells.

Synapse assembly inhibition was in part due to reduced TCR signaling and pMHC clustering at the T cell-bilayer interface, suggesting that protein N interferes withpMHC-TCR interactions. Moreover, N protein co-localized with theTCR independently of pMHC, consistent with a possible interaction with TCR complex components. Based on these data, we concludethat hRSV N protein expression at the cell surface of infected cells inhibits T cell activation. These data suggest that inhibition ofsynapse assembly can be a major virulence factor that contributes to impairing acquired immunity and enhances susceptibility to reinfection by hRSV. These data allowed the generation of an RSV vaccine, which showed protection in several animal models and now is about to enter evaluation in human clinical trials.