Bacterial Membrane Vesicles | Encyclopedia MDPI

Bacterial Membrane Vesicles: History

Please note this is an old version of this entry, which may differ significantly from the current revision.

Subjects: Microbiology

Contributor: Renata Godlewska

Pathogenic bacteria interact with cells of their host via many factors. The surface components, i.e., adhesins, lipoproteins, LPS and glycoconjugates, are particularly important in the initial stages of colonization. They enable adhesion and multiplication, as well as the formation of biofilms. In contrast, virulence factors such as invasins and toxins act quickly to damage host cells, causing tissue destruction and, consequently, organ dysfunction. These proteins must be exported from the bacterium and delivered to the host cell in order to function effectively. Bacteria have developed a number of one- and two-step secretion systems to transport their proteins to target cells. Several authors have postulated the existence of another transport system (sometimes called “secretion system type zero”), which utilizes extracellular structures, namely membrane vesicles (MVs).

membrane vesicle
virulence factors
secretion systems
pathogenesis
bacterial toxins

1. Introduction

The first report of bacterial membrane vesicles appeared in the mid-twentieth century ^[1]. In this study, the protein exotoxin secreted by Vibrio cholerae was shown to be resistant to proteases. Transmission electron microscope (TEM) analysis suggested that this exotoxin is located within spherical structures containing components of the bacterial cell envelope. These structures, detected in cell-free supernatants obtained from liquid bacterial cultures in the exponential growth phase ^[2], were named membrane vesicles (MVs).

As enveloped structures, MVs have the characteristics of vectors that enable the transport of substances highly sensitive to environmental conditions. They protect proteins enclosed in their lumen against enzymatic decomposition, degradation related to low or high pH and oxidative stress conditions. Therefore, it is not surprising that, in addition to proteins acquiring of nutrients from the environment, pathogenic bacteria also use MVs to transport toxins that directly affect host cells and enzymes promoting bacterial colonization, facilitating the disruption of infected tissues and spreading of infection in the host. We provide examples of the best characterized bacterial virulence factors associated with MVs in Table 1. The enrichment of certain proteins in MVs, at a higher concentration than found in bacteria, suggests a degree of specification for MVs in toxic activity, polymer decomposition, antibiotic inactivation or metal ion sequestration. The small size of MVs (ranging from 20–250 nm in diameter) ^[3] permits them to overcome epithelial barriers, such as the gut–blood barrier (GBB), and enter tissues that are not colonized by the bacteria producing them. The presence of surface antigens allows MVs to interact with cells of the host immune system, so that virulence factors they transport can modulate (induce or inhibit) the immune response. MVs can also act as “traps” for antibodies circulating in the inhabited tissue, or for bacteriophages in the natural environment. The great versatility of vesicles is the result of variation in their structure and composition. The secretion of active factors in this form is one of the most complex and diverse mechanisms of bacterial interaction with the environment and other cells ^[4].

2. Structure of Membrane Vesicles (MVs) and Mechanisms of Secretion

The production of MVs (both extracellular and intracellular) has been observed in organisms from all three domains of life ^[5]. Research on bacterial vesicles has been ongoing for over 60 years, but the mechanisms of their biogenesis are still not fully understood. Several vesicle types have been described in Gram-negative and Gram-positive bacteria. The MVs exhibit the membrane features of the originating bacteria and thus could indicate the nature of their cargos, such as proteins and nucleic acids (Figure 1).

Figure 1. Mechanisms of bacterial membrane vesicle formation. In gram-negative bacteria, membrane vesicles are produced through membrane blebbing or explosive cell lysis triggered by phage-derived endolysins. Endolysins participate in the formation of cytoplasmic membrane vesicles (CMVs) in Gram-positive bacteria. The cytoplasmic membrane protrudes through holes in the peptidoglycan degraded by phage-derived endolysins. The contents of the membrane vesicles depends on the route of their formation. EMV—explosive membrane vesicle; OIMV—outer-inner membrane vesicle; OMV—outer membrane vesicle; CMV—cytoplasmic membrane vesicle.

OMVs (outer-membrane vesicles) produced by Gram-negative bacteria consist of blebs of bacterial outer membrane containing transmembrane proteins and LPS, with extracellular DNA (eDNA) exposed on the surface of OMVs, with periplasmic content packaged in the lumen of the vesicle. OMVs are produced by many species of pathogenic bacteria, including Neisseria meningitidis, Helicobacter pylori, Escherichia coli (EHEC) and Salmonella spp. ^[6]. Increased secretion of OMVs usually occurs under stressful conditions, and is accompanied with the accumulation of misfolded proteins in the periplasm. According to one MV biogenesis model, the pressure of these defective proteins on the inner surface of the OM is responsible for bulging of the membrane and its detachment from the cell in the form of vesicles ^[7].

Outer-inner membrane vesicles (OIMVs) are double-membrane structures and were first observed in cultures of Pseudomonas aeruginosa ^[8]. The outer membrane and inner membrane are separated with a thin layer of periplasm with degraded fragments of peptidoglycan. The production of OIMVs are induced in stressful or adverse situations. Cytoplasm present in the lumen of these vesicles contains proteins and also fragments of DNA derived from the chromosome or plasmids and ATP ^[8].

Vesicles containing cytoplasm are also produced by Gram-positive bacteria. The release of CMVs (cytoplasmic membrane vesicles) requires local peptidoglycan degradation by internal or external lytic enzymes (digesting both the glycan backbone and peptide bonds in the amino acid chains) ^[9]. CMV production has been observed in several model Gram-positive bacteria, including Bacillus subtilis ^[10], Bacillus anthracis and Staphylococcus aureus ^[11]^[12].

The last membrane vesicle type is EMVs (explosive membrane vesicles), which are the most diverse in terms of structure. They arise spontaneously during bacterial cell lysis. Fragments of membrane, together with the outflow of cytoplasm (also periplasm in the case of Gram-negative bacteria), create spherical membrane structures in the environment. Thus, the process of EMV “assembly” is cell-independent and spontaneous, so bacteria are unable to control the content of these vesicles. As a result, each lysing cell produces MVs that differ in size, composition and function. This process has been described in P. aeruginosa biofilms, where deeply located cells subjected to hypoxia, nutrient deficiency and activation of the SOS system are autolysed through the activity of endolysins, and type R and F pyocins ^[13]. EMVs released in this way are an important factor in the virulence of pathogenic P. aeruginosa strains. As a component of the biofilm matrix, they bind eDNA and polysaccharides, and also bacteria via surface adhesins, which stiffens this structure ^[14].

Several recent reviews describe the composition and biogenesis of bacterial membrane vesicles ^[6]^[7]^[15]^[16]^[17]. In this article we present the latest data concerning interactions between MVs and selected human cell types.

3. Conclusions

The molecular understanding of bacterial virulence factors is an important challenge for microbiologists. Modern techniques have enabled the discovery of novel mechanisms that sometimes surprise researchers with their universality. This is the case for membrane vesicles, which play important roles in the interactions of bacteria with cells of other organisms. MVs are not only a new type of secretion system, their great variety of structure and function, action at a distance, and stability in the host system make them an important weapon in the bacterial arsenal. Examples of the best characterized bacterial virulence factors associated with MVs are presented below in Table 1.

Table 1. Examples of bacteria producing membrane vesicles and active factors discovered inside/outside MVs.

Bacterial Species (Gram-Negative)	Active Factors	Reference
Acholeplasma laidlawii PG8	adhesins/invasins—enable tight physical contact between bacterium and host cell ABC transporting complexes hydrolases: proteases, nucleases, and glycosylases metallo-β-lactamase	^[18]
Acinetobacter baumannii	AmpC—β-lactamase OmpA—porin with potential cytotoxic features	^[19]
Actinobacillus pleuropneumoniae	Apx—exotoxin with cytolytic features	^[20]
Aggregatibacter actinomycetemcomitans	leucotoxin (Ltx)—induces lysis of monocytes and neutrophils AbOmpA—porin that enables transport of soluble substances in MV lumen across membrane	^[21]
Bartonella henselae	HbpC—protein accumulating hemin; hemin sequestration protects bacteria from toxic concentrations of this porphyrin	^[22]
Borrelia burgdorferi	enolases—enzymes cleave plasminogen to plasmin active form OspA/B/D—lipoprotein; promotes adhesion of OMVs to host cells (especially cells of endothelium)	^[23]^[24]
Burkholderia cepacia	spreading factors—non-specific lipases and proteases (including metallo-proteases)	^[25]
Campylobacter jejuni	CDT—three-component genotoxin (CdtA/B/C) with endonuclease features, stops cell cycle at G2/M phase check-point	^[26]
Coxiella burnetti	periplasmic effector proteins	^[27]
Escherichia coli K1	OmpA—interaction with Ecgp receptor on surface of brain microvascular endothelium leads to cell invasion; may also act in trans to promote cell invasion by other bacterial species K1 antigen—polysaccharide antigen from cell envelope, linear polymer of NeuNac TLR ligands—flagellin, lipoproteins, poly-CpG DNA strands	^[28]
Escherichia coli O157: H7 Shigella dysenteriae	Shiga toxin (Stx1/2)—toxin from AB5 group with RNA-N-glycosylases activity; stops eukaryotic translation	^[29]
enterotoxic E. coli (ETEC)	thermolabile toxin (LT)—activates adenylate cyclase to elevate cAMP levels which disturbs water management of host cell; form linked to OMVs may also be non-febrile adhesin	^[30]
enterohemorrhagic E. coli (EHEC)	ClyA—pore-forming cytolysin; reducing environment of OMV lumen promotes ClyA oligomerization to produce active complex HlyA—alpha-hemolysin; damages enterocyte mitochondrial membranes	^[31]
extraintestinal pathogenic E. coli (ExPEC)	HlyA—alpha-hemolysin CNF1—cell necrosis factor	^[32]
Haemophilus influenzae type B (Hib)	LPS and other strong surface antigens proteins that assist in process of biofilm formation	^[33]
Legionella pneumophila	Map—acidic phosphatase ProA1—metallo-protease LasB—elastase legionaminic acid—component of LPS O-antigen inhibitors of phagosome-lysosome fusion	^[34]
Moraxella catarrhalis	MID—protein linking IgD, superantigen UspA1/2—blocks C3 protein of complement system Bro1/2—beta-lactamase	^[35]
Neisseria meningitidis serogroup B	PorA—main surface antigen of OMVs; potential component of future vaccine LpxL1—strong adjuvant	^[36]
Porphyromonas gingivalis	gingipains—non-specific proteases degrading elements of host’s tissue and cytokines HmuY—lipoprotein accumulating heme; assists biofilm formation process factors assisting in co-localization with Treponema denticola	^[37]
Salmonella enterica	SopB—protects SCV (Salmonella-containing vacuoles) from degradation by reorganization of actin cytoskeleton SipC—protein assisting in cell invasion process SopA—ubiquitin ligase (E3) disturbing ubiquitin pathway of host cell FljB—flagellin, strong antigen SopE2—guanine nucleotide exchange factor (GEF); by catalysing exchange GDP → GTP disturbs function of Rho-protein family GTPases controlling dynamics of host cell cytoskeleton, which leads to membrane surface deformation and assists invasion process PagK1/2—exact function still unknown; probably assists bacterial proliferation inside SCV SrfN—promotes bacterial survival inside macrophages	^[38]
Shigella flexneri	IpaD—controls cell invasion process IutA—iron-siderophore receptor	^[39]
Treponema denticola	dentilisin—protease	^[40]
Vibrio cholerae	cholera toxin (CTx)—AB₅ group toxin; disturbs ion-transfer across cell membranes and water management	^[41]
Yersinia pestis	Ail—surface adhesin; promotes contact with host cells Pla—extracellular protease; activator of plasminogen Caf1—fimbrial antigen F1; main component of OMVs	^[42]
Bacterial Species (Gram-Positive)	Active Factors	Citations
Bacillus anthracis	anthrolysin (ALO)—cholesterol-dependent cytolysin lethal factor (LF)—zinc-protease; hydrolyses several MAPK-kinases (MAPKK), causes disturbance of signalling pathways and cell death edema factor (ED)—calmodulin- and Ca²⁺-dependent adenylate cyclase; induces uncontrolled increase in cAMP concentration in phagocytic cells thus depleting ATP reserves	^{[ 12 ]}
Clostridium perfringens	N-acetyloglukozamina — ważny czynnik prozapalny	^{[ 43 ]}
Enterokok faecium	fosfolipidy; zmniejszyć działanie przeciwbakteryjne antybiotyku daptomycyny SdrD — białko wiążące kolagen PavA — białko wiążące fibronektynę AtlA – autolizyna; wspomaga proces powstawania biofilmu Acm — MSCRAMM (składniki powierzchni drobnoustrojów rozpoznające cząsteczki matrycy adhezyjnej) z grupy adhezyny; wiąże kolagen Fnm — adhezyna wiążąca fibronektynę PsaA – lipoproteina; potencjalny składnik przyszłej szczepionki	^{[ 44 ]}
Prątek gruźlicy	LpqH — lipoproteina; asystuje w procesach transportowych MPB83 — wysoce immunogenna glikoproteina LprA — lipoproteina; silny agonista TLR2 PSTS3 — element systemu transportowego ABC związany z importem jonów fosforu lipoarabinomannan (LAM) — glikolipid powierzchniowy o właściwościach anty-ROS mykobaktyna – powierzchnia Fe ³⁺ -syderofor	^{[ 45 ]}
Propionibacterium acnes	czynniki aktywujące zapalenie zależne od TLR2	^{[ 46 ]}
Streptococcus mutans	eDNA — ważny składnik biofilmu glukozylotransferazy (GtfB/C/D) — wytwarzają adhezyjne zewnątrzkomórkowe polisacharydy z substratu sacharozy kwas lipotejchojowy (LTA) – antygen powierzchniowy; ważny w procesie adsorpcji w tworzeniu biofilmu	^{[ 47 ]}
Streptococcus pneumoniae	TatD — nieswoista DNaza umożliwiająca degradację NET (sieci DNA związane z białkami o działaniu przeciwdrobnoustrojowym: LL37, mieloperoksydaza, elastaza neutrofili) EndA — nieswoista DNaza zlokalizowana na powierzchni MV PspC-białko wiążące czynnik H; blokuje alternatywny szlak dopełniacza pneumolizyna (Ply) – egzotoksyna o właściwościach cytolitycznych PsaA – adhezyna; silny antygen powierzchniowy SatA — transporter typu ABC; antygen powierzchniowy AmiA — białko wiążące peptydy; asystuje w aktywnym transporcie MalX — białko wiążące maltozę i maltodekstrynę PnrA — transporter nukleozydów typu ABC spr1909 — białko wiążące penicylinę	^{[ 48 ]}

This entry is adapted from the peer-reviewed paper 10.3390/toxins13120845

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