IGF1R is an entry receptor for respiratory syncytial virus

Nature. 2020 Jul;583(7817):615-619. doi: 10.1038/s41586-020-2369-7. Epub 2020 Jun 3.

Abstract

Pneumonia resulting from infection is one of the leading causes of death worldwide. Pulmonary infection by the respiratory syncytial virus (RSV) is a large burden on human health, for which there are few therapeutic options1. RSV targets ciliated epithelial cells in the airways, but how viruses such as RSV interact with receptors on these cells is not understood. Nucleolin is an entry coreceptor for RSV2 and also mediates the cellular entry of influenza, the parainfluenza virus, some enteroviruses and the bacterium that causes tularaemia3,4. Here we show a mechanism of RSV entry into cells in which outside-in signalling, involving binding of the prefusion RSV-F glycoprotein with the insulin-like growth factor-1 receptor, triggers the activation of protein kinase C zeta (PKCζ). This cellular signalling cascade recruits nucleolin from the nuclei of cells to the plasma membrane, where it also binds to RSV-F on virions. We find that inhibiting PKCζ activation prevents the trafficking of nucleolin to RSV particles on airway organoid cultures, and reduces viral replication and pathology in RSV-infected mice. These findings reveal a mechanism of virus entry in which receptor engagement and signal transduction bring the coreceptor to viral particles at the cell surface, and could form the basis of new therapeutics to treat RSV infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Nucleus / metabolism
  • Enzyme Activation
  • Humans
  • Membrane Fusion / drug effects
  • Phosphoproteins / metabolism
  • Protein Binding
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • RNA-Binding Proteins / metabolism
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Receptor, IGF Type 1 / metabolism*
  • Receptors, Virus / metabolism*
  • Respiratory Syncytial Viruses / drug effects
  • Respiratory Syncytial Viruses / metabolism*
  • Respiratory Syncytial Viruses / pathogenicity
  • Respiratory Syncytial Viruses / physiology
  • Viral Load / drug effects
  • Virus Internalization* / drug effects

Substances

  • IGF1R protein, human
  • Phosphoproteins
  • RNA-Binding Proteins
  • Receptors, Virus
  • nucleolin
  • Receptor, IGF Type 1
  • protein kinase C zeta
  • Protein Kinase C