Multiscale study of the interactions between corona viruses of various pathogenicity and cell membrane components in the early stages of virus entry

Description du projet

Étude des mécanismes d’entrée cellulaire pour des coronavirus de pathogénicité différente

Les coronavirus (CoV) ont été à l’origine de plusieurs épidémies, dont l’actuelle pandémie mondiale. Certains virus de cette famille ne provoquent que des affections bénignes, et les raisons des variations de la gravité des maladies sont mal comprises. Les CoV se fixent aux cellules par une interaction spécifique entre la glycoprotéine spike (CoV‑S) et les récepteurs de la surface cellulaire. Le projet CoVentry, financé par l’UE, étudie le mécanisme d’entrée précoce de SARS‑CoV, SARS‑CoV2 et hCoV‑NL63, des variants de pathogénicité différents, qui partagent le même récepteur cellulaire, l’enzyme de conversion de l’angiotensine 2. Le projet se concentre sur la caractérisation des interactions des virus avec la surface cellulaire, y compris les liaisons entre les S‑CoV individuels et les composants membranaires uniques, et les interactions multivalentes à la surface cellulaire.

Objectif

Coronaviruses (CoV) have been responsible for several severe viral outbreaks culminating in the current global pandemic. However, some viruses of this family are widespread and only cause mild conditions, like the common cold. The origin of the significant variation in the severity of the CoV-related diseases is still poorly understood. Recent studies have suggested that the strength of the interaction between the virus and the cell surface during the early stages of virus entry could play an important role. CoVs attachment to the plasma membrane is mediated by the specific interaction between the viral spike glycoprotein (CoV-S) and receptors found on the cell surface. In addition, several CoVs have been shown to interact with the cellular glycocalyx during the early attachment to the cell surface. In this proposal, I describe the study of the early entry mechanism of CoV-SARS, CoV-SARS2, and hCoV-NL63 which all target the same cellular receptor, angiotensin-converting enzyme 2, while strongly varying in their pathogenicity. The study focuses on the dynamics, kinetics and strength of the interaction of these viruses with the cell surface. It employs an incremental approach, from the study of the bond between individual CoV-S and single membrane components to multivalent interactions between the virion and the cell surface. A wide array of biophysical (e.g. single-particle tracking, and optical tweezer) and biological (e.g. viral pseudotypes) techniques are used, combining the host’s and my expertise. This multidisciplinary project will result in a unique and comprehensive characterisation of the interactions taking place during CoV-entry, it will elucidate the difference between viral species, and it will give insights into the origin of the observed differences in pathogenicity. In addition, this work will strengthen and expand my experience and network in the virology and biophysics fields, significantly improving my career prospects as an independent researcher.