Scientists at the Institut Laue-Langevin (ILL), in collaboration with the Paul Scherrer Institut (PSI), the Institut de Biologie Structurale (IBS) and the Australian Nuclear Science and Technology Organisation (ANSTO), have published new data on how the SARS-CoV-2 spike protein interacts with mammalian lung cell membranes, allowing the viral RNA to enter human cells.
The purpose of the SARS-CoV-2 spike protein is relatively well understood. The glycoprotein is responsible for the fusion event that allows the virus to enter human cells and cause infection and, for this reason, it has been the focus for most Covid-19 vaccines.
“A lot of research has focused on the interaction between the virus spike protein and the angiotensin-converting enzyme 2 (ACE2) for which there are many receptors on cell surfaces in the lungs,” said Prof Giovanna Fragneto, Large Scale Structures Group Leader at ILL. “What is less well understood is how the spike protein interacts with the rest of the cell membrane. Our expertise in creating model cell membranes and the enormous resolving power offered to us by neutron reflectometry meant that we were uniquely positioned to explore these wider interactions.”
The team produced systems that excluded some of the proteins found in real cell membranes so that the individual contribution of each component could be more easily understood. Fragneto continued: “We saw an unexpected large change in the composition of the lipid bilayer, compatible with an increase of water content, as soon as we introduced the stable spike protein (sSpike) and we saw this with and without the presence of soluble ACE2. Combining this information with the previous knowledge that lipid pockets can stabilise the spike protein closed structure, we concluded that sSpike is able to significantly strip away lipids from the cell membrane, disrupting and potentially entering directly through the membrane.”
Dr Samantha Micciulla said: “Until recently, it just hasn’t been possible to create complex model cell membranes and investigate structural interactions at the nanometre level. Neutron reflectometry allows us sub-nanometre levels of resolution, enabling differentiation even between different atomic isotopes, so we can fully interrogate the molecular interactions between sSpike and different elements of the membrane.”
Prof. Fragneto concludes: “This direct interaction with the lipid bilayer on the cell surface could provide insight for the development of more effective therapeutics or future vaccines. Of course, this is fundamental research, and we are far from using this in a pharmaceutical application; however, this study provides additional understanding that will be important to virology studies in the future, for SARS-CoV-2 and beyond.”