Enveloped viruses such as SARS-CoV-2 interact closely with the membranes of their host cells throughout their life cycle. They use the cell membrane to enter and exit the cell, and their lipid envelope is entirely derived from the host. The composition and organization of the viral membrane are therefore of central importance for viral infectivity. Numerous studies have shown that viruses specifically manipulate lipid metabolism and lipid dynamics in host cells, both during the assembly of new viral particles and during cell entry. However, little is still known about how viruses interact with complex intracellular membranes, in particular with the endoplasmic reticulum–Golgi intermediate compartment (ERGIC), where the assembly of many viruses takes place.

The NanoLipoVirus project investigates the role of host lipids in viral assembly and entry. Key questions include whether the lipid composition of the viral envelope is primarily determined by the membranes of the ERGIC or by viral structural proteins, how specific lipids influence the mobility of viral envelope proteins and thus infectivity, and how they contribute to endocytosis and membrane fusion during cell entry.

To address these questions, the project combines dynamic super-resolution microscopy in living cells with newly developed functional membrane probes and fluorescent SARS-CoV-2 particles. The studies range from model virus-like particles to wild-type viruses. A particular focus is placed on lipids beyond cholesterol, whose role in the assembly and fusion of SARS-CoV-2 remains largely unclear.

In the first phase of the project, new fluorescent tools are developed to visualize lipid–virus interactions during infection. These include fluorescent virus-like particles, molecular probes for ER, ERGIC and Golgi membranes, and adapted advanced fluorescence microscopy techniques. Building on this, the project will (i) determine the lipid composition of virus particles using lipidomics, (ii) analyze lipid organization and their interactions with viral structural proteins using environment-sensitive probes, (iii) monitor changes in lipid dynamics in living cells down to the single-molecule level, and (iv) selectively modify virus-like particles to decipher the interplay between identified lipids and viral envelope proteins during receptor recognition and cell entry by fusion or endocytosis.

By closely integrating virology, membrane biophysics, dynamic super-resolution microscopy and the development of innovative fluorescent probes, NanoLipoVirus contributes to a fundamental understanding of how viruses manipulate internal cellular membranes. The expected results will elucidate, at the molecular level, how host lipids control viral assembly and facilitate entry into new host cells.