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Review
, 13 (10), 620-30

Through the Wall: Extracellular Vesicles in Gram-positive Bacteria, Mycobacteria and Fungi

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Review

Through the Wall: Extracellular Vesicles in Gram-positive Bacteria, Mycobacteria and Fungi

Lisa Brown et al. Nat Rev Microbiol.

Abstract

Extracellular vesicles (EVs) are produced by all domains of life. In Gram-negative bacteria, EVs are produced by the pinching off of the outer membrane; however, how EVs escape the thick cell walls of Gram-positive bacteria, mycobacteria and fungi is still unknown. Nonetheless, EVs have been described in a variety of cell-walled organisms, including Staphylococcus aureus, Mycobacterium tuberculosis and Cryptococcus neoformans. These EVs contain varied cargo, including nucleic acids, toxins, lipoproteins and enzymes, and have important roles in microbial physiology and pathogenesis. In this Review, we describe the current status of vesiculogenesis research in thick-walled microorganisms and discuss the cargo and functions associated with EVs in these species.

Figures

Figure 1
Figure 1. Cell wall structure of Gram-negative bacteria, Gram-positive bacteria, mycobacteria and fungi
a | The cell wall of Gram-negative bacteria consists of a thin layer of peptidoglycan in the periplasmic space between the inner and outer lipid membranes. The outer membrane contains lipopolysaccharides on its outer leaflet and facilitates non-vesicle-mediated transport through channels such as porins or specialized transporters. It is thought that vesicles from these organisms are produced by the pinching off of the outer membrane, resulting in outer-membrane vesicles (OMVs),–. The lack of an outer membrane, as well as the presence of a thick cell wall, in Gram-positive bacteria, mycobacteria and fungi led to a long-standing belief that these organisms did not produce extracellular vesicles. b | Gram-positive bacteria have a single lipid membrane surrounded by a cell wall composed of a thick layer of peptidoglycan and lipoteichoic acid, which is anchored to the cell membrane by diacylglycerol. c | Cell walls of mycobacteria consist of thin layers of peptidoglycan and arabinogalactan, and a thick layer of mycolic acids. Glycolipids and porins are also found in these cell walls, as is lipoarabinomannan, which is anchored to the cell membrane by diacylglycerol. This cell wall surrounds a single lipid membrane. d | A single plasma membrane is also present in fungi, surrounded by a cell wall consisting of various layers of the polysaccharides chitin, β-glucan and mannan (in the form of mannoproteins).
Figure 2
Figure 2. Extracellular vesicle formation and release: three non-mutually exclusive hypotheses
Three hypotheses explain possible non-mutually exclusive mechanisms by which extracellular vesicles (EVs) traverse thick cell walls. a | EVs may be forced through the wall by turgor pressure after release from the plasma membrane. Pore size or cell wall thickness may regulate the size and ability of EVs to pass through the cell wall,. b | Cell wall-modifying enzymes released with EVs may ‘loosen’ the wall and increase pore size to facilitate EV release. Preparations of EVs from both fungi and Gram-positive bacteria include cell wall-modifying enzymes,. c | Protein channels or structural cables may guide EVs to the extracellular environment. Proteomic data show that many fungal EV preparations contain tubulin and/or actin, which are components of structural cables (not shown),. Figure 3
Figure 3
Figure 3. Extracellular vesicle function
Extracellular vesicles (EVs) contain a varied array of factors, depending on the organism in question, and thus have several functions. a | Some microbial pathogens use EVs to transport virulence factors or to modulate the host immune response. Clostridium perfringens packages chromosomal DNA into EVs, including genes that encode toxins. EVs produced by mycobacteria contain ligands that are recognized by Toll-like receptors (TLRs) in the plasma membrane of host cells. For example, triacylated lipoproteins on the outer leaflet of Mycobacterium tuberculosis EVs are recognized by TLR1–TLR2 heterodimers. After TLR binding, the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signalling pathways are activated, leading to cytokine production. However, a prolonged activation of these pathways can lead to the repression of genes involved in antigen presentation. Bacillus anthracis concentrates anthrax toxins into EVs that are thought to deliver the intraluminal contents directly into the host cell cytoplasm by fusing with cholesterol microdomains in the host cell membrane. b | Subpopulations of EVs might be retained in the microbial cell wall to deliver materials that are required for cell wall synthesis and maintenance. In melanizing fungi, laccase is an important enzyme involved in the synthesis of the protective melanin polymer contained in the cell wall. Laccase has been identified in EVs produced by these fungi, and it has been proposed that these laccase-containing EVs are retained in the cell wall to enable in situ melanin synthesis.

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