For certain viruses, the pH environment provides a cue for conformational changes in glycoproteins initiating fusion

For certain viruses, the pH environment provides a cue for conformational changes in glycoproteins initiating fusion. pursue therapies involving EVs and delivering their cargo, a better grasp of EV targeting is needed. Here, we review recent progress in understanding the molecular mechanisms underpinning EV uptake by receptor-ligand interactions with recipient cells, highlighting once again the overlap of EVs and viruses. Despite their highly heterogeneous nature, EVs require common viral entry pathways, and an unanticipated specificity for cargo delivery is being revealed. We discuss the challenges ahead in delineating specific roles for EV-associated ligands and cellular receptors. INTRODUCTION Viruses and extracellular vesicles (EVs) are heterogeneous, mostly submicron-sized biological particles produced by living, metazoan cells; they are capable of intercellular transfer of Costunolide biological materials and genetic information. While the machineries that produce viruses and EVs in mammalian cells have many commonalities (1), viruses have been presumed to be unique in their ability to replicate a genome in host cells. Enveloped viruses cover their capsid structure Costunolide in a surrounding, host-derived membrane, while envelope proteins on the surface coordinate cellular tropism (2). Nonenveloped viruses have an outer protein coat that is resistant to harsh conditions, such as dryness and extreme pH or temperature. These viruses are often virulent, causing host cell lysis upon virion release. Recent observations have challenged the traditional classification of enveloped and nonenveloped viruses. It appears that both enveloped and nonenveloped viruses have evolved with ingenious cell entry mechanisms, hijacking host cellular membranes for genome delivery into selected permissive cells. Thus, the distinctions between viruses and certain types of EVs are blurring. These recent insights fit with the increasing Costunolide realization that viruses exploit EVs for several purposes: (i) to enter host cells, (ii) to promote viral spread, and (iii) to avoid immune responses. The contribution of EVs to viral infections may have broad implications for future vaccine PCDH8 development (3, 4). A compelling argument for EVs having a role in viral infections is that EVs produced by virus-infected cells have altered physiological properties (5), for example, interfering with, rather than triggering, immunological responses (6). Apart from incorporating viral proteins, recent studies have indicated that EVs can contain virus-derived nucleic acids, including functional, noncoding microRNAs (miRNAs) (7, 8). Despite major advances in EV research concerning molecular characterization, EV cell entry mechanisms have received less attention, and it has remained unclear if selective cell targeting is achieved and how, for example, EV RNA content is delivered. Recent studies have begun to address a portion of these questions by looking at biodistribution upon intravenous administration of purified EV populations, but these studies have so far not revealed highly specific targeting mechanisms (9). One explanation could be that such studies have typically relied on administering nonphysiological amounts of purified EV preparations. Despite limitations, selectivity in EV targeting has been revealed between astrocytes and microglia (10) in mice, in experiments with purified astrocyte-derived EVs, although appropriate control EVs from a different cell type, such as neurons or completely unrelated immune cell exosomes, were not used. In a more recent study, it was shown that specific integrin expression patterns on EVs may cause specific target cell selection (11). EV targeting was also demonstrated with genetic mouse models that made use of the Cre-lox system with defined donor and recipient cells (12,C14). This innovative strategy, successfully employed by independent groups in different mouse models, has demonstrated that functional cell-cell RNA transfer can occur via EVs, providing new opportunities to study EV targeting and entry mechanisms in a physiological context. Nevertheless, many molecular details await elucidation. In contrast, viral entry mechanisms that are mediated by specific receptors have been broadly studied both and and how to discern the.