In the frame of this ERC, we first were able to demonstrate that viral infection is a multiple steps process which involved the cooperativity of multiple cell surface receptors. In particular, we evidenced, for reoviruses, that the first binding step to cell surface-exposed sialic acid (a particular glycan present at the cell surface) serves as a switch to further engage specific entry receptors (Koehler et al, Nat. Commun. (2019)), leading in turn to the specific recruitment of clathrin (Koehler et al, Nat. Commun (2021)), activating the virus entry within the host cell. This observation was possible due to the development of a new biophysical platform in virology which combines atomic force microscopy and high-resolution confocal microscopy (Renard et al., Nat. Commun. (2020)).
The crucial role of glycans during the virus early binding steps was also demonstrated for the herpes virus, an enveloped virus (for a review of the role of glycans in viral infection see Ann. Rev. Virol. (2020)). We introduced a new method to force-probe multivalent attachment directly on living cells, and we showed, for the first time, direct evidence of a new mechanism by which herpesvirus surface glycoprotein acts as a key negative regulator in the first step of binding to cell surface glycans. This work published in Science Advances (2018), shed new light on the infection mechanism and how the virus itself regulates its binding toward controlling the entry and release scenarios and its diffusion at the cell surface.
Our findings, underlying the crucial role of attachment factor to control the infectivity of viruses, provided us with a unique opportunity to manipulate virus binding efficiency and infectivity for vaccine and oncolytic applications. In this context, we filled in a patent (EP19152640.9).
In response to the Covid-19 pandemic, we also investigated how SARS-CoV-2 interacts with host cells. In a first study (Yang et al, Nat. Commun, 2020), a few months after its emergence, we were able to characterize the kinetic and thermodynamic properties of the spike protein interaction with the ACE2 receptor both in vitro and in a cellular context. This study was a milestone in the field and is among the 50 most downloaded papers in the journal Nature Communications in 2020. Based on this study, we then monitored the impact of the new variants on this binding step and at the end of 2021 (Koehler et al., Nat. Commun., 2021), we showed that the mechanisms of the new variants and in particular the Kappa variant (close to Delta) showed a new binding mechanism that could notably reduce the efficacy of the first version of the vaccine. Based on our initial study on SARS-CoV-2 characterizing the binding of SARS-CoV-2 in the cellular context, we observed that, apart from ACE2, other binding events occurred very rapidly. We were able to show that sialic acids, an in particular 9-O-acetylated sialic acids, played an important role in early binding events. We then developed a multivalent molecule with multiple copies of this sialic acid and demonstrated that this molecule was very effective in preventing SARS-CoV-2 binding. We then showed that it significantly reduced the infection of cells by the virus (Petitjean et al, Nat. Commun. 2022). This molecule has been patented (EP21195975.4) and we are currently conducting, in collaboration with the University of Liège (Belgium), tests in mice which suggest promising activity in vivo.
