Pro- and anti-viral functions of Extracellular Vesicles released during picornavirus infection

Upon recognizing an invading virus, cells employ an arsenal of antiviral molecules to limit viral replication and spread. Besides the production of antiviral cytokines, such as type I interferons, virus infections also induce cells to release extracellular vesicles (EV) containing viral components. Recent findings indicate that viruses of the Picornaviridae family can use these EV to escape from intact cells in the pre-lytic phase of infection. These virus-containing EV have been proposed to either facilitate virus spreading or induce antiviral immunity, but mechanistic understanding of these processes is lacking. We recently discovered that infection with a picornavirus not only leads to the escape of virions enclosed in EV, but also to the timed release of various other EV subpopulations. Awareness of heterogeneity in virus-induced EV is essential to further delineate their role in infection, as distinct pro-viral or pro-host functions may be ascribed to different EV subpopulations. The proposed research aims to classify different EV subpopulations released from picornavirus-infected cells based on their capacity to spread virus infection or to induce antiviral immune responses. This functional differentiation will be related to differences in the molecular contents of these EV subsets, i.e. the presence of host and viral proteins/RNAs with pro- or anti-viral functions. Using different picornavirus types and several primary cell types susceptible to these viruses, we will also investigate whether the anti-/pro-viral activity provided by EV subpopulations is virus type- and host cell type-specific or not.

With this research we aim to acquire a thorough understanding of how virus-infected cells use EV to communicate to neighbouring cells in order to regulate the antiviral response and/or spreading of the virus. This is highly relevant for optimization of antiviral therapies and for vaccine research.