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Communication between immune cells via release of RNA-carrying vesicles: Lessons from viruses

Final Report Summary - INTERCOM (Communication between immune cells via release of RNA-carrying vesicles: Lessons from viruses)

To effectively raise and regulate immune responses, immune cells exchange information by intercellular communication. A recently discovered means of communication is via the release of small lipid membrane-enclosed particles, called ‘extracellular vesicles’ (EV). These EV contain RNA, which uniquely allows cells to exchange genetically encoded messages that can induce long-term effects in target cells. The INTERCOM project aimed to assess how diverse immune-related stimuli control the RNA content of released EV, and to understand functional consequences of this process.
INTERCOM provides several lines of evidence that a complex set of different RNA classes and proteins are packaged in EV and that these molecular contents are highly variable. We show that immune activating and immune dampening signals trigger the same cell type to release EV with substantial differences in RNA content. We discovered that not only the well-known class of microRNAs, but also other RNA classes, such as the highly conserved Y-RNAs, contributed to the molecular signature of EV. Our findings clearly indicate that changes in cell status induced by the cellular environment stimulate the release of EV that are heterogeneous in their molecular contents. Understanding the heterogeneity of EV is essential for unraveling the function of EV and for biomarker research. In the INTERCOM project, we developed and applied highly advanced single EV detection and isolation methods allowing the assessment of EV heterogeneity.
To demonstrate whether and how diversity in EV composition translates to functional diversity, we made use of infections with non-enveloped (naked) viruses. We discovered that these viruses trigger multiple pathways for EV formation and release. In in vitro cell systems and in human plasma we observed that the virus-host interactions induce temporal and compositional heterogeneity in the protein and RNA contents of EV. Particular subsets of EV released during infection contain complete virus particles and allow viruses to escape from infected cells early during infection and resist immune responses. On a single vesicle basis, we demonstrated that EV released during infection vary largely in potency of transferring virus infection. The data underscore that it is vital to analyze the heterogeneity in EV release and molecular composition over the course of infection to be able to understand the role of EV in virus dissemination and antiviral host responses.
Overall, the INTERCOM studies broaden our view on the type of molecular messages conveyed by EV, provide knowledge and tools for analyzing EV heterogeneity in health and disease, and deliver molecular insight in how viruses modify EV-mediated communication between cells.