In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.

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Biological properties of extracellular vesicles and their physiological functions

Gram-negative bacteria characteristically are surrounded by an additional membrane layer, the outer membrane. Although outer membrane components often play important roles in the interaction of symbiotic or pathogenic bacteria with their host organisms, the major role of this membrane must usually be to serve as a permeability barrier to prevent the entry of noxious compounds and at the same time to allow the influx of nutrient molecules. This review summarizes the development in the field since our previous review (H. Nikaido and M. Vaara, Microbiol. Rev. 49:1-32, 1985) was published. With the discovery of protein channels, structural knowledge enables us to understand in molecular detail how porins, specific channels, TonB-linked receptors, and other proteins function. We are now beginning to see how the export of large proteins occurs across the outer membrane. With our knowledge of the lipopolysaccharide-phospholipid asymmetric bilayer of the outer membrane, we are finally beginning to understand how this bilayer can retard the entry of lipophilic compounds, owing to our increasing knowledge about the chemistry of lipopolysaccharide from diverse organisms and the way in which lipopolysaccharide structure is modified by environmental conditions.

Molecular Basis of Bacterial Outer Membrane Permeability Revisited

Both eukaryotic and prokaryotic cells release small, phospholipid-enclosed vesicles into their environment. Why do cells release vesicles? Initial studies showed that eukaryotic vesicles are used to remove obsolete cellular molecules. Although this release of vesicles is beneficial to the cell, the vesicles can also be a danger to their environment, for instance in blood, where vesicles can provide a surface supporting coagulation. Evidence is accumulating that vesicles are cargo containers used by eukaryotic cells to exchange biomolecules as transmembrane receptors and genetic information. Because also bacteria communicate to each other via extracellular vesicles, the intercellular communication via extracellular cargo carriers seems to be conserved throughout evolution, and therefore vesicles are likely to be a highly efficient, robust, and economic manner of exchanging information between cells. Furthermore, vesicles protect cells from accumulation of waste or drugs, they contribute to physiology and pathology, and they have a myriad of potential clinical applications, ranging from biomarkers to anticancer therapy. Because vesicles may pass the blood-brain barrier, they can perhaps even be considered naturally occurring liposomes. Unfortunately, pathways of vesicle release and vesicles themselves are also being used by tumors and infectious diseases to facilitate spreading, and to escape from immune surveillance. In this review, the different types, nomenclature, functions, and clinical relevance of vesicles will be discussed.

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Classification, Functions, and Clinical Relevance of Extracellular Vesicles

Gram-negative bacteria produce outer membrane vesicles (OMVs) that contain biologically active proteins and perform diverse biological processes. Unlike other secretion mechanisms, OMVs enable bacteria to secrete insoluble molecules in addition to and in complex with soluble material. OMVs allow enzymes to reach distant targets in a concentrated, protected, and targeted form. OMVs also play roles in bacterial survival: Their production is a bacterial stress response and important for nutrient acquisition, biofilm development, and pathogenesis. Key characteristics of OMV biogenesis include outward bulging of areas lacking membrane-peptidoglycan bonds, the capacity to upregulate vesicle production without also losing outer membrane integrity, enrichment or exclusion of certain proteins and lipids, and membrane fission without direct energy from ATP/GTP hydrolysis. Comparisons of similar budding mechanisms from diverse biological domains have provided new insight into evaluating mechanisms for outer membrane vesiculation.

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Biological functions and biogenesis of secreted bacterial outer membrane vesicles.

Extracellular secretion of products is the major mechanism by which Gram-negative pathogens communicate with and intoxicate host cells. Vesicles released from the envelope of growing bacteria serve as secretory vehicles for proteins and lipids of Gram-negative bacteria. Vesicle production occurs in infected tissues and is influenced by environmental factors. Vesicles play roles in establishing a colonization niche, carrying and transmitting virulence factors into host cells, and modulating host defense and response. Vesicle-mediated toxin delivery is a potent virulence mechanism exhibited by diverse Gram-negative pathogens. The biochemical and functional properties of pathogen-derived vesicles reveal their potential to critically impact disease.

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Bacterial outer membrane vesicles and the host–pathogen interaction

Many gram-negative bacteria produce membrane vesicles, suggesting that vesicle production is not purposeless; indeed, studies during the last two decades have presented strong evidence supporting the importance of vesicles. Typical vesicles released from the surfaces of gram-negative bacteria are 50 to 250 nm, spherical, and made up of outer membrane and encapsulated periplasmic components (4, 26). Vesicle components include outer membrane proteins, lipopolysaccharide, periplasmic proteins, phospholipids, DNA, and RNA (9, 12, 15, 22, 34, 40). Vesicles from gram-negative bacteria were reported to fuse to both gram-positive and gram-negative bacteria and in some instances to promote lysis of the target cell (28). Moreover, vesicles may function as an alternative secretory pathway (3, 23) and promote adherence of the parent cell to host cells (17, 32). By virtue of their small size, bilayer protecting envelope, and ability to integrate into the membranes of foreign bacteria and to adhere to or be engulfed by eukaryotic cells, a potential role of vesicles in delivery of virulence factors, including enzymes and toxins, is not unlikely (23). In fact, virulence factors associated with the parent strain, including proteases, phospholipases, autolysin, hemolysins, and Shiga toxins, have been isolated from vesicles (3, 22, 26, 28).

Aside from toxic compounds, DNA has also been isolated from vesicles. Vesicles produced by Pseudomonas aeruginosa were reported to contain DNA (22). Vesicles released by Neisseria gonorrhoeae harbor both linear and circular DNA, including 4.2- and 7.1-kb plasmids (12). Chromosomal and bacteriophage-associated virulence genes were detected in Escherichia coli O157:H7 vesicles (26). Moreover, this research demonstrated that DNA was protected from digestion by DNase, suggesting that DNA is packaged within vesicles (26).

Bacterial evolution often proceeds by horizontal gene transfer between different genera and species (1, 7). Antibiotic resistance genes and pathogenicity islands have been acquired by a variety of pathogens, including E. coli, Salmonella enterica serovar Typhimurium, Yersinia pestis, Dichelobacter nodosis, and Helicobacter pylori (19). Virulence factors contributing to the pathogenicity of E. coli O157:H7, including Shiga toxins (45, 46) and intimin (31, 44), are encoded on pathogenicity islands in the O157 chromosome and are thought to have been acquired by horizontal transfer. Results of previous studies suggest that vesicles may be involved in the transfer of genetic material among similar bacterial species (8, 12, 26). The hypothesis has been put forth that vesicles influence antibiotic resistance in other bacteria in two ways: by physical dissemination of preformed antibiotic-inactivating enzymes into the recipient periplasm and by delivery of antibiotic resistance plasmids (3, 12). Competent Haemophilus influenzae produces vesicles which are released into the medium when cells are returned to normal growth conditions or a noncompetent state (8). Specific DNA-binding peptides were reported to be present on the surfaces of H. influenzae vesicles (24, 25) and to be associated with vesicles from N. gonorrhoeae (11).

Previously, it was reported that vesicles released by E. coli O157:H7 into culture medium contain virulence genes and Shiga toxin (26). In the present study, we demonstrate that E. coli O157:H7 vesicles mediate the transfer of virulence genes, which are subsequently expressed by recipient enteric bacteria. Moreover, the origin of the DNA in E. coli O157:H7 vesicles is elucidated. Observations show that in addition to bacteriophage-associated genes, E. coli O157:H7 vesicles contain plasmids and fragments of chromosomal DNA.

Vesicle-Mediated Transfer of Virulence Genes from Escherichia coli O157:H7 to Other Enteric Bacteria

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Vesicle-Mediated Transfer of Virulence Genes from Escherichia coli O157:H7 to Other Enteric Bacteria