Outer membrane vesicles (OMVs) are nanoscale proteoliposomes secreted from the cell envelope of all Gram-negative bacteria. Originally considered as an artifact of the cell wall, OMVs are now recognized as a general secretion system, which serves to improve the fitness of bacteria and facilitate bacterial interactions in polymicrobial communities as well as interactions between the microbe and the host. In general, OMVs are released in increased amounts from pathogenic bacteria and have been found to harbor much of the contents of the parental bacterium. They mainly encompass components of the outer membrane and the periplasm including various virulence factors such as toxins, adhesins, and immunomodulatory molecules. Numerous studies have clearly shown that the delivery of toxins and other virulence factors via OMVs essentially influences their interactions with host cells. Here, we review the OMV-mediated intracellular deployment of toxins and other virulence factors with a special focus on intestinal pathogenic Escherichia coli. Especially, OMVs ubiquitously produced and secreted by enterohemorrhagic E. coli (EHEC) appear as a highly advanced mechanism for secretion and simultaneous, coordinated and direct delivery of bacterial virulence factors into host cells. OMV-associated virulence factors are not only stabilized by the association with OMVs, but can also often target previously unknown target structures and perform novel activities. The toxins are released by OMVs in their active forms and are transported via cell sorting processes to their specific cell compartments, where they can develop their detrimental effects. OMVs can be considered as bacterial "long distance weapons" that attack host tissues and help bacterial pathogens to establish the colonization of their biological niche(s), impair host cell function, and modulate the defense of the host. Thus, OMVs contribute significantly to the virulence of the pathogenic bacteria.

Center for Molecular Biology of Inflammation Institute of Infectiology University of Muenster Münster Germany

Institute for Hygiene University Hospital of Muenster University of Muenster Münster Germany

National Institute of Public Health Reference Laboratory for E coli and Shigellae Prague Czechia

Zobrazit více v PubMed

Aldick T., Bielaszewska M., Uhlin B. E., Humpf H. U., Wai S. N., Karch H. (2009). Vesicular stabilization and activity augmentation of enterohaemorrhagic PubMed DOI

Amano A., Takeuchi H., Furuta N. (2010). Outer membrane vesicles function as offensive weapons in host-parasite interactions. Microbes Infect. 12, 791–798. 10.1016/j.micinf.2010.05.008 PubMed DOI

Balsalobre C., Silván J. M., Berglund S., Mizunoe Y., Uhlin B. E., Wai S. N. (2006). Release of the type I secreted alpha-haemolysin via outer membrane vesicles from PubMed DOI

Bauwens A., Kunsmann L., Karch H., Mellmann A., Bielaszewska M. (2017a). Antibiotic-mediated modulations of outer membrane vesicles in enterohemorrhagic PubMed DOI PMC

Bauwens A., Kunsmann L., Marejkova M., Zhang W., Karch H., Bielaszewska M., et al. (2017b). Intrahost milieu modulates production of outer membrane vesicles, vesicle-associated Shiga toxin 2a and cytotoxicity in PubMed DOI

Bielaszewska M., Marejkova M., Bauwens A., Kunsmann-Prokscha L., Mellmann A., Karch H. (2018). Enterohemorrhagic PubMed DOI

Bielaszewska M., Rüter C., Bauwens A., Greune L., Jarosch K. A., Steil D., et al. (2017). Host cell interactions of outer membrane vesicle-associated virulence factors of enterohemorrhagic PubMed DOI PMC

Bielaszewska M., Rüter C., Kunsmann L., Greune L., Bauwens A., Zhang W., et al. (2013). Enterohemorrhagic PubMed DOI PMC

Bomberger J. M., MacEachran D. P., Coutermarsh B. A., Ye S. Y., O'Toole G. A., Stanton B. A. (2009). Long-distance delivery of bacterial virulence factors by PubMed DOI PMC

Bonnington K. E., Kuehn M. J. (2014). Protein selection and export via outer membrane vesicles. Biochim. Biophys. Acta Mol. Cell Res. 1843, 1612–1619. 10.1016/j.bbamcr.2013.12.011 PubMed DOI PMC

Chatterjee D., Chaudhuri K. (2011). Association of cholera toxin with PubMed DOI

Chatterjee S., Mondal A., Mitra S., Basu S. (2017). PubMed DOI

Chattopadhyay M. K., Jagannadham M. V. (2015). Vesicles-mediated resistance to antibiotics in bacteria. Front. Microbiol. 6:974 10.3389/fmicb.2015.00974 PubMed DOI PMC

Ciofu O., Beveridge T. J., Kadurugamuwa J., Walther-Rasmussen J., Høiby N. (2000). Chromosomal beta-lactamase is packaged into membrane vesicles and secreted from PubMed DOI

Devos S., Stremersch S., Raemdonck K., Braeckmans K., Devreese B. (2016). Intra- and interspecies effects of outer membrane vesicles from PubMed DOI PMC

Devos S., Van Putte W., Vitse J., Van Driessche G., Stremersch S., Van Den Broek W., et al. (2017). Membrane vesicle secretion and prophage induction in multidrug-resistant PubMed DOI

Domingues S., Nielsen K. M. (2017). Membrane vesicles and horizontal gene transfer in prokaryotes. Curr. Opin. Microbiol. 38, 16–21. 10.1016/j.mib.2017.03.012 PubMed DOI

Duperthuy M., Sjöström A. E., Sabharwal D., Damghani F., Uhlin B. E., Wai S. N. (2013). Role of the vibrio cholerae matrix protein Bap1 in cross-resistance to antimicrobial peptides. PLoS Pathog. 9:e1003620. 10.1371/journal.ppat.1003620 PubMed DOI PMC

Elhenawy W., Bording-Jorgensen M., Valguarnera E., Haurat M. F., Wine E., Feldman M. F. (2016). LPS remodeling triggers formation of outer membrane vesicles in PubMed DOI PMC

Ellis T. N., Kuehn M. J. (2010). Virulence and immunomodulatory roles of bacterial outer membrane vesicles. Microbiol. Mol. Biol. Rev. 74, 81–94. 10.1128/MMBR.00031-09 PubMed DOI PMC

Elluri S., Enow C., Vdovikova S., Rompikuntal P. K., Dongre M., Carlsson S., et al. (2014). Outer membrane vesicles mediate transport of biologically active PubMed DOI PMC

Fabrega M. J., Rodriguez-Nogales A., Garrido-Mesa J., Algieri F., Badia J., Gimenez R., et al. (2017). Intestinal anti-inflammatory effects of outer membrane vesicles from PubMed DOI PMC

Fingermann M., Avila L., De Marco M. B., Vazquez L., Di Biase D. N., Muller A. V., et al. (2018). OMV-based vaccine formulations against Shiga toxin producing PubMed DOI PMC

Fiocca R., Necchi V., Sommi P., Ricci V., Telford J., Cover T. L., et al. (1999). Release of PubMed DOI

Fleckenstein J. M., Kuhlmann F. M. (2019). Enterotoxigenic PubMed DOI PMC

Fulsundar S., Harms K., Flaten G. E., Johnsen P. J., Chopade B. A., Nielsen K. M. (2014). Gene transfer potential of outer membrane vesicles of PubMed DOI PMC

González L. J., Bahr G., Nakashige T. G., Nolan E. M., Bonomo R. A., Vila A. J. (2016). Membrane anchoring stabilizes and favors secretion of New Delhi metallo-β-lactamase. Nat. Chem. Biol. 12, 516–522. 10.1038/nchembio.2083 PubMed DOI PMC

Guerrero-Mandujano A., Hernandez-Cortez C., Ibarra J. A., Castro-Escarpulli G. (2017). The outer membrane vesicles: secretion system type zero. Traffic 18, 425–432. 10.1111/tra.12488 PubMed DOI

Guidi R., Levi L., Rouf S. F., Puiac S., Rhen M., Frisan T. (2013). PubMed DOI

Haurat M. F., Elhenawy W., Feldman M. F. (2015). Prokaryotic membrane vesicles: new insights on biogenesis and biological roles. Biol. Chem. 396, 95–109. 10.1515/hsz-2014-0183 PubMed DOI

Hays M. P., Houben D., Yang Y., Luirink J., Hardwidge P. R. (2018). Immunization with Skp delivered on outer membrane vesicles protects mice against enterotoxigenic PubMed DOI PMC

Hellman J., Loiselle P. M., Zanzot E. M., Allaire J. E., Tehan M. M., Boyle L. A., et al. (2000). Release of gram-negative outer-membrane proteins into human serum and septic rat blood and their interactions with immunoglobulin in antiserum to PubMed DOI

Horstman A. L., Kuehn M. J. (2000). Enterotoxigenic PubMed DOI PMC

Horstman A. L., Kuehn M. J. (2002). Bacterial surface association of heat-labile enterotoxin through lipopolysaccharide after secretion via the general secretory pathway. J. Biol. Chem. 277, 32538–32545. 10.1074/jbc.M203740200 PubMed DOI PMC

Jan A. T. (2017). Outer Membrane Vesicles (OMVs) of gram-negative bacteria. PubMed DOI PMC

Kadurugamuwa J. L., Beveridge T. J. (1995). Virulence factors are released from PubMed DOI PMC

Kadurugamuwa J. L., Beveridge T. J. (1997). Natural release of virulence factors in membrane vesicles by PubMed DOI

Kaparakis M., Turnbull L., Carneiro L., Firth S., Coleman H. A., Parkington H. C., et al. (2010). Bacterial membrane vesicles deliver peptidoglycan to NOD1 in epithelial cells. Cell. Microbiol. 12, 372–385. 10.1111/j.1462-5822.2009.01404.x PubMed DOI

Karch H., Tarr P. I., Bielaszewska M. (2005). Enterohaemorrhagic PubMed DOI

Karpman D., Loos S., Tati R., Arvidsson I. (2017). Haemolytic uraemic syndrome. J. Inter. Med. 281, 123–148. 10.1111/joim.12546 PubMed DOI

Kato S., Kowashi Y., Demuth D. R. (2002). Outer membrane-like vesicles secreted by PubMed DOI

Keenan J. I., Allardyce R. A. (2000). Iron influences the expression of PubMed DOI

Kesty N. C., Kuehn M. J. (2004). Incorporation of heterologous outer membrane and periplasmic proteins into PubMed DOI PMC

Kesty N. C., Mason K. M., Reedy M., Miller S. E., Kuehn M. J. (2004). Enterotoxigenic escherichia coli vesicles target toxin delivery into mammalian cells. EMBO J. 23, 4538–4549. 10.1038/sj.emboj.7600471 PubMed DOI PMC

Kim S. H., Lee Y. H., Lee S. H., Lee S. R., Huh J. W., Kim S. U., et al. (2011). Mouse model for hemolytic uremic syndrome induced by outer membrane vesicles of PubMed DOI

Kim S. W., Park S. B., Im S. P., Lee J. S., Jung J. W., Gong T. W., et al. (2018). Outer membrane vesicles from β-lactam-resistant PubMed DOI PMC

Kolling G. L., Matthews K. R. (1999). Export of virulence genes and shiga toxin by membrane vesicles of PubMed DOI PMC

Kouokam J. C., Wai S. N., Fallman M., Dobrindt U., Hacker J., Uhlin B. E. (2006). Active cytotoxic necrotizing factor 1 associated with outer membrane vesicles from uropathogenic PubMed DOI PMC

Kulp A., Kuehn M. J. (2010). Biological functions and biogenesis of secreted bacterial outer membrane vesicles. Annu. Rev. Microbiol. 64, 163–184. 10.1146/annurev.micro.091208.073413 PubMed DOI PMC

Kunsmann L., Rüter C., Bauwens A., Greune L., Gluder M., Kemper B., et al. (2015). Virulence from vesicles: novel mechanisms of host cell injury by PubMed DOI PMC

Leitner D. R., Lichtenegger S., Temel P., Zingl F. G., Ratzberger D., Roier S., et al. (2015). A combined vaccine approach against PubMed DOI PMC

Lindmark B., Rompikuntal P. K., Vaitkevicius K., Song T. Y., Mizunoe Y., Uhlin B. E., et al. (2009). Outer membrane vesicle-mediated release of cytolethal distending toxin (CDT) from PubMed DOI PMC

Liu Q., Yi J., Liang K., Zhang X. M. (2017). PubMed DOI

MacDonald I. A., Kuehn M. J. (2012). Offense and defense: microbial membrane vesicles play both ways. Res. Microbiol. 163, 607–618. 10.1016/j.resmic.2012.10.020 PubMed DOI PMC

Manning A. J., Kuehn M. J. (2011). Contribution of bacterial outer membrane vesicles to innate bacterial defense. BMC Microbiol. 11:258. 10.1186/1471-2180-11-258 PubMed DOI PMC

Maredia R., Devineni N., Lentz P., Dallo S. F., Yu J. J., Guentzel N., et al. (2012). Vesiculation from PubMed DOI PMC

Marsay L., Dold C., Green C. A., Rollier C. S., Norheim G., Sadarangani M., et al. (2015). A novel meningococcal outer membrane vesicle vaccine with constitutive expression of FetA: a phase I clinical trial. J. Infect. 71, 326–337. 10.1016/j.jinf.2015.05.006 PubMed DOI PMC

Mirhoseini A., Amani J., Nazarian S. (2018). Review on pathogenicity mechanism of enterotoxigenic PubMed DOI

Namork E., Brandtzaeg P. (2002). Fatal meningococcal septicaemia with “blebbing” meningococcus. Lancet 360, 1741–1741. 10.1016/S0140-6736(02)11721-1 PubMed DOI

O'Donoghue E. J., Krachler A. M. (2016). Mechanisms of outer membrane vesicle entry into host cells. Cell. Microbiol. 18, 1508–1517. 10.1111/cmi.12655 PubMed DOI PMC

Orench-Rivera N., Kuehn M. J. (2016). Environmentally controlled bacterial vesicle-mediated export. Cell. Microbiol. 18, 1525–1536. 10.1111/cmi.12676 PubMed DOI PMC

Park K. S., Choi K. H., Kim Y. S., Hong B. S., Kim O. Y., Kim J. H., et al. (2010). Outer membrane vesicles derived from PubMed DOI PMC

Pérez-Cruz C., Carrión O., Delgado L., Martinez G., López-Iglesias C., Mercade E. (2013). New type of outer membrane vesicle produced by the Gram-negative bacterium Shewanella vesiculosa M7T: implications for DNA content. Appl. Environ. Microbiol. 79, 1874–1881. 10.1128/AEM.03657-12 PubMed DOI PMC

Pérez-Cruz C., Delgado L., López-Iglesias C., Mercade E. (2015). Outer-inner membrane vesicles naturally secreted by gram-negative pathogenic bacteria. PLoS ONE 10:e0116896. 10.1371/journal.pone.0116896 PubMed DOI PMC

Petousis-Harris H., Paynter J., Morgan J., Saxton P., McArdle B., Goodyear-Smith F., et al. (2017). Effectiveness of a group B outer membrane vesicle meningococcal vaccine against gonorrhoea in New Zealand: a retrospective case-control study. Lancet 390, 1603–1610. 10.1016/S0140-6736(17)31449-6 PubMed DOI

Rewatkar P. V., Parton R. G., Parekh H. S., Parat M. O. (2015). Are caveolae a cellular entry route for non-viral therapeutic delivery systems? Adv. Drug Deliv. Rev. 91, 92–108. 10.1016/j.addr.2015.01.003 PubMed DOI

Reyes-Robles T., Dillard R. S., Cairns L. S., Silva-Valenzuela C. A., Housman M., Ali A., et al. (2018). PubMed DOI PMC

Roier S., Zingl F. G., Cakar F., Schild S. (2016). Bacterial outer membrane vesicle biogenesis: a new mechanism and its implications. Microb. Cell. 3, 257–259. 10.15698/mic2016.06.508 PubMed DOI PMC

Rolhion N., Barnich N., Bringer M. A., Glasser A. L., Ranc J., Hébuterne X., et al. (2010). Abnormally expressed ER stress response chaperone Gp96 in CD favours adherent-invasive escherichia coli invasion. Gut 59, 1355–1362. 10.1136/gut.2010.207456 PubMed DOI PMC

Rompikuntal P. K., Thay B., Khan M. K., Alanko J., Penttinen A. M., Asikainen S., et al. (2012). Perinuclear localization of internalized outer membrane vesicles carrying active cytolethal distending toxin from PubMed DOI PMC

Rompikuntal P. K., Vdovikova S., Duperthuy M., Johnson T. L., Ahlund M., Lundmark R., et al. (2015). Outer membrane vesicle-mediated export of processed PrtV protease from PubMed DOI PMC

Roy K., Bartels S., Qadri F., Fleckenstein J. M. (2010). Enterotoxigenic PubMed DOI PMC

Roy K., Hamilton D. J., Munson G. P., Fleckenstein J. M. (2011). Outer membrane vesicles induce immune responses to virulence proteins and protect against colonization by enterotoxigenic PubMed DOI PMC

Rumbo C., Fernández-Moreira E., Merino M., Poza M., Mendez J. A., Soares N. C., et al. (2011). Horizontal transfer of the OXA-24 carbapenemase gene via outer membrane vesicles: a new mechanism of dissemination of carbapenem resistance genes in PubMed DOI PMC

Rüter C., Lubos M. L., Norkowski S., Schmidt M. A. (2018). All in-Multiple parallel strategies for intracellular delivery by bacterial pathogens. Inter. J. Med. Microbiol. 308, 872–881. 10.1016/j.ijmm.2018.06.007 PubMed DOI

Schaar V., de Vries S. P. W., Vidakovics M., Bootsma H. J., Larsson L., Hermans P. W. M., et al. (2011). Multicomponent PubMed DOI

Schaar V., Uddback I., Nordstrom T., Riesbeck K. (2014). Group a streptococci are protected from amoxicillin-mediated killing by vesicles containing beta-lactamase derived from PubMed DOI

Schwechheimer C., Kuehn M. J. (2015). Outer-membrane vesicles from gram-negative bacteria: biogenesis and functions. Nat. Rev. Microbiol. 13, 605–619. 10.1038/nrmicro3525 PubMed DOI PMC

Shah B., Sullivan C. J., Lonergan N. E., Stanley S., Soult M. C., Britt L. D. (2012). Circulating bacterial membrane cesicles cause sepsis in rats. Shock 37, 621–628. 10.1097/SHK.0b013e318250de5d PubMed DOI

Stentz R., Horn N., Cross K., Salt L., Brearley C., Livermore D. M., et al. (2015). Cephalosporinases associated with outer membrane vesicles released by PubMed DOI PMC

Stephens D. S., Edwards K. M., Morris F., McGee Z. A. (1982). Pili and outer-membrane appendages on PubMed DOI

Svennerholm K., Park K. S., Wikstrom J., Lasser C., Crescitelli R., Shelke G. V., et al. (2017). PubMed DOI PMC

Tan T. T., Morgelin M., Forsgren A., Riesbeck K. (2007). PubMed DOI

Tarr P. I., Gordon C. A., Chandler W. L. (2005). Shiga-toxin-producing PubMed DOI

Thay B., Damm A., Kufer T. A., Wai S. N., Oscarsson J. (2014). PubMed DOI PMC

Toyofuku M., Nomura N., Eberl L. (2019). Types and origins of bacterial membrane vesicles. Nat. Rev. Microbiol. 17, 13–24. 10.1038/s41579-018-0112-2 PubMed DOI

Turnbull L., Toyofuku M., Hynen A. L., Kurosawa M., Pessi G., Petty N. K., et al. (2016). Explosive cell lysis as a mechanism for the biogenesis of bacterial membrane vesicles and biofilms. Nat. Commun. 7:11220. 10.1038/ncomms11220 PubMed DOI PMC

Urashima A., Sanou A., Yen H., Tobe T. (2017). Enterohaemorrhagic escherichia coli produces outer membrane vesicles as an active defence system against antimicrobial peptide LL-37. Cell. Microbiol. 19:e12758. 10.1111/cmi.12758 PubMed DOI

Vanaja S. K., Russo A. J., Behl B., Banerjee I., Yankova M., Deshmukh S. D., et al. (2016). Bacterial outer membrane vesicles mediate cytosolic localization of LPS and caspase-11 activation. Cell 165, 1106–1119. 10.1016/j.cell.2016.04.015 PubMed DOI PMC

Wai S. N., Lindmark B., Soderblom T., Takade A., Westermark M., Oscarsson J., et al. (2003). Vesicle-mediated export and assembly of pore-forming oligomers of the enterobacterial ClyA cytotoxin. Cell 115, 25–35. 10.1016/S0092-8674(03)00754-2 PubMed DOI

Wai S. N., Takade A., Amako K. (1995). The release of outer-membrane vesicles from the strains of enterotoxigenic PubMed DOI

Wang E. H., Liu Y. K., Qiu X. H., Tang Y. T., Wang H. D., Xiao X. Z., et al. (2019). Bacteria-released outer membrane vesicles promote disseminated intravascular coagulation. Thromb. Res. 178, 26–33. 10.1016/j.thromres.2019.03.019 PubMed DOI

Yokoyama K., Horii T., Yamashino T., Hashikawa S., Barua S., Hasegawa T., et al. (2000). Production of shiga toxin by PubMed DOI

Zoja C., Buelli S., Morigi M. (2010). Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial dysfunction. Pediatr. Nephrol. 25, 2231–2240. 10.1007/s00467-010-1522-1 PubMed DOI

Enterohemorrhagic Escherichia coli O157 outer membrane vesicles administered by oral gavage cause renal tubular injury and acute kidney failure in mice

Translocation of outer membrane vesicles from enterohemorrhagic Escherichia coli O157 across the intestinal epithelial barrier

In Vivo Secretion of β-Lactamase-Carrying Outer Membrane Vesicles as a Mechanism of β-Lactam Therapy Failure