Interactions between viral factories and cellular innate immunity, a story of liquid biocondensates
Yves Gaudin (I2BC)
Replication of Mononegavirales (MNV) occurs in viral factories which form inclusions in the host-cell cytoplasm. For rabies virus (RABV), those inclusions are called Negri Bodies (NBs). NBs have characteristics similar to those of liquid organelles: they are spherical, they fuse to form larger structures, and they disappear upon hypotonic shock. Their liquid phase was confirmed by FRAP experiments. Live-cell imaging indicates that viral nucleocapsids are ejected from NBs and transported along microtubules to form either new virions or secondary viral factories.
We developed several minimal systems (both cellular and acellular) allowing the formation of biomolecular condensates recapitulating NBs properties. Those minimal systems established RABV phosphoprotein (P) as the main regulator of the liquid liquid phase separation (LLPS) and identified structural elements of RABV nucleoprotein and P that are key in this process. Formation of liquid viral factories by LLPS has been extended to other MNV. This is a paradigm change in the field of MNV replication that invites us to revisit the interplay between viral factories and innate cellular immunity.
As an example, we previously demonstrated that stress granules, which are also liquid biomolecular condensates containing microbes-associated-molecular-patterns recognition receptors acting as sensors of RNA virus replication, come into close contact with NBs, exchange material with them, but do not fully mix their content. We have now extended those observations to other components of the cellular pathway leading to interferon production demonstrating a key role of viral and cellular biomolecular condensates in innate immunity.