Reverse engineering viral factories

The main intracellular manifestation of viruses is the factories they set up to mass-produce viral genomes for new virus particles.

For positive-sense RNA viruses, these factories (here called replication organelles) are created on cellular membranes as an intimate union of viral and cellular components.

Their intracellular, membrane-bound nature has made replication organelles difficult to study using canonical, single-discipline approaches.

Here, we will investigate the hypothesis that the replication organelles of a vast phylum of viruses share deeply conserved, underlying physical principles.

To do so, we will apply a novel combination of disciplines to the side-by-side analysis of two virus genera – alphaviruses and flaviviruses - for the identification of genus-specific and conserved principles.

Integrating cryo-electron tomography with analytical and numerical mathematical models, we will determine the structures of replication organelles directly in infected cells and correlate these structures with energetics and mechanisms.

A combination of precise membrane lipid manipulations in live infected cells, novel proteomics methods and mathematical modelling will reveal which membrane compositions promote or inhibit replication organelle activity.

Finally, we will use and develop AI-based design of interface-disrupting, protein-binding proteins to probe the role of individual protein-protein interactions for replication organelle biogenesis and activity.