Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery

Abstract

SUMMARYExtracellular vesicles (EVs) have emerged as crucial mediators of intercellular communication, being involved in a wide array of key biological processes. Eukaryotic cells, and also bacteria, actively release heterogeneous subtypes of EVs into the extracellular space, where their contents reflect their (sub)cellular origin and the physiologic state of the parent cell. Within the past 20 years, presumed subtypes of EVs have been given a rather confusing diversity of names, including exosomes, microvesicles, ectosomes, microparticles, virosomes, virus-like particles, and oncosomes, and these names are variously defined by biogenesis, physical characteristics, or function. The latter category, functions, in particular the transmission of biological signals between cellsin vivoand how EVs control biological processes, has garnered much interest. EVs have pathophysiological properties in cancer, neurodegenerative disorders, infectious disease, and cardiovascular disease, highlighting possibilities not only for minimally invasive diagnostic applications but also for therapeutic interventions, like macromolecular drug delivery. Yet, in order to 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.

Glycosylated extracellular vesicles released by glioblastoma cells are decorated by CCL18 allowing for cellular uptake via chemokine receptor CCR8

“…Co-localisation studies and assays employing pathway-specific inhibitors revealed involvement of both clathrin-dependent and clathrin-independent endocytosis, including caveolin-mediated endocytosis, macropinocytosis and phagocytosis [22]. These observations seem compatible with receptor-mediated EV uptake mechanisms, similar as for many enveloped viruses [29,30]. To date only few specific cellular receptors for EVs have been proposed.…”

The Role of Exosomal VP40 in Ebola Virus Disease

“…The upregulation of various host molecules derived from exosomes (i.e., CD81, CD63, and CD9) by several viruses and incorporation into the viral membrane for various purposes have been previously described (Dongen et al, 2016). For example, CD63 upregulation during HIV-1 infection has been suggested to mediate CD63 integration into HIV-1 membranes to aid in both viral fusion and replication (Li et al, 2011(Li et al, , 2014Narayanan et al, 2013;Fu et al, 2015;Sampey et al, 2016).…”

Exosomes in Viral Disease

“…For the purposes of this review, we will focus our discussion on exosomes; however, there are several excellent reviews in the literature that address Electronic supplementary material The online version of this article (doi:10.1007/s13311-016-0450-6) contains supplementary material, which is available to authorized users. extracellular vesicles as a whole [6][7][8][9][10][11]. In appearance, exosomes are unilamellar vesicles composed of a lipid bilayer that have a homogenous cup-shaped appearance on scanning electromicroscopy [3,12].…”