Mapping individual multi-molecular interactions provides new insights into virus capture

Understanding the early molecular events leading to viral capture and cell entry is critical for designing effective vaccines. To elucidate how a receptor in the cell membrane binds and captures a virus, information at the single molecular level is essential. However, molecules rarely act isolated; their function depends on interactions with other molecules. One can think of them as a society, where individual behaviour strongly depends on the interactions with others. Exactly the same happens in a cell: interactions between individual molecules lie at the core of their function.  However, visualizing interactions between multiple molecules in real-time, at the single molecule level and in living cells is tremendously challenging. Therefore, developing suitable tools that provide access to real-time molecular interactions has long been a priority in biophysics. In our recent ACS Nano paper we report on a new and powerful multi-colour single molecule methodology to monitor different labelled molecules simultaneously in living cells. Using this technique, we captured interactions between individual virus-like particles and three different proteins on the membrane of immature dendritic cells. This mapping revealed a coordinated action of the three proteins that was crucial to capture and to increase the internalization of two different viruses: HIV-1 and Sars-CoV-2, responsible for COVID-19.  Our findings suggest a potential generalized mechanism for virus capture and has consequences for vaccine development, since preventing the early stages of viral capture by disrupting interactions between the different proteins could be a more effective strategy than blocking the viral receptor alone. Importantly, our breakthrough technology paves the way towards the study of many other multi-molecular interactions in living cells, an important step towards understanding how molecular interactions regulate function in (patho)physiological conditions.