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

Descripción del proyecto

Estudio de los mecanismos de entrada celular para los coronavirus con distinta patogenia

Se han producido numerosos brotes de coronavirus (CoV), incluida la pandemia actual. Algunos virus de esta familia solo producen enfermedades leves, y no se conocen bien las causas de las variaciones en cuanto a la gravedad de las enfermedades. Los CoV se fijan a las células a través de una interacción específica entre la proteína espicular (CoV-S) del virus y los receptores presentes en la superficie celular. El proyecto CoVentry, financiado con fondos europeos, investiga los mecanismos iniciales de entrada del coronavirus del síndrome respiratorio agudo grave (SARS-CoV), el coronavirus del síndrome respiratorio agudo grave de tipo 2 (SARS-CoV-2) y el coronavirus humano NL63 (HCoV-NL63), variantes con distinta patogenia que comparten el mismo receptor celular: la enzima convertidora de la angiotensina 2. El proyecto se centra en la caracterización de las interacciones de los virus con la superficie celular, lo que incluye los enlaces entre las CoV-S individuales y los componentes de una sola membrana y las interacciones multivalentes en la superficie celular.

Objetivo

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.