Editors' ChoiceVirology

Facilitating RSV entry

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Science Signaling  28 Jul 2020:
Vol. 13, Issue 642, eabd9986
DOI: 10.1126/scisignal.abd9986

Binding of respiratory syncytial virus to the receptor IGF-1R stimulates viral entry in a PKCζ-dependent manner.

Respiratory syncytial virus (RSV) infects ciliated bronchial epithelial cells, causing pulmonary infections for which there are limited available therapies. RSV infection is mediated by binding of the RSV fusion (RSV-F) glycoprotein to the nucleolar protein nucleolin, which interacts with the virus at the plasma membrane. Through in vitro infection assays, Griffiths et al. showed that RSV efficiently infected cells that had small amounts of nucleolin at the plasma membrane. Imaging flow cytometry revealed that RSV and nucleolin colocalized into patches at the cell surface, which correlated with the trafficking of nucleolin from the nucleus to the plasma membrane. RSV-F interacted with insulin-like growth factor 1 receptor (IGF-1R). Both an inhibitor and a blocking antibody against IGF-1R reduced RSV infection, whereas treatment with IGF-1 enhanced infection. Overexpression of human IGF-1R in mosquito cells, which are refractive to RSV infection, rendered the cells infectable. Investigation of the signaling pathways downstream of IGF-1R revealed that inhibition of the kinase PKCζ reduced the amount of RSV that bound to the cell surface and inhibited viral infection. Live-cell imaging showed that inhibition of PKCζ or knockdown of IGF-1R inhibited RSV-cell fusion. In cultured organoids derived from human bronchial epithelial cells, IGF-1R, nucleolin, and RSV colocalized at the apical surface after infection, a distribution that was blocked by a peptide-based PKCζ inhibitor. Compared to control mice, those treated with the PKCζ inhibitor 1 day after RSV infection showed decreased inflammation, viral load, and lung pathology. Together, these data identify IGF-1R as a primary receptor for RSV and suggest PKCζ as a potential therapeutic target for treating RSV.

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