Invité direction: Irina Gutsche, IBS Grenoble -« Cracking the code of the Respiratory Syncytial Virus Nucleocapsids with cryo-EM »

Résumé

Respiratory syncytial virus (RSV) is the leading cause of child bronchiolitis and pneumonia, with a burden
on the elderly comparable to that of influenza. Although prophylactic options such as vaccines and
monoclonal antibodies have recently become available, no direct-acting RSV antiviral exists to date.
Replication and transcription of RSV genetic material are critical steps for establishing and spreading
infection, making them attractive therapeutic targets. These functions take place inside cytoplasmic
membranelles biocondensates called viral factories and are carried out by the viral ribonucleoprotein
particles, composed of the viral genomic RNA enwrapped by the viral nucleoprotein into a helical
nucleocapsid, and the RNA-dependent RNA polymerase complex. In this talk, we will dive into the
structural landscape of the RSV nucleocapsids and explore the molecular mechanisms and extent of
their polymorphism by assessing the effects of a range of targeted mutations using single particle cryo-
electron microscopy. We will also see how a single mutation that mimics a post-translational
modification of the nucleocapsid that we have recently identified in RSV infected cells can dramatically
affect the nucleocapsid properties. In addition, we will have a first glimpse into the structures and the
spatial organisation of the nucleocapsids within the viral factories of RSV-infected cells using cryo-
electron tomography. This ongoing work marks a new step towards elucidating the structural origins
and the functional implications of the non-canonical helical symmetry of RSV nucleocapsids. We hope
that it will serve as a foundation for investigating dynamic conformational changes of the RSV RNA
synthesis machinery during transcription and replication. But for now, every new structure we solve
raises more questions than it answers, making us realise that we are only scratching the surface and
that fully understanding the molecular mechanisms of RSV genome synthesis is still a long way off.