The Role of Bacterial Membrane Vesicles in Human Health and Disease

Abstract

Bacterial membrane vesicles (MVs) are nanoparticles derived from the membrane components of bacteria that transport microbial derived substances. MVs are ubiquitous across a variety of terrestrial and marine environments and vary widely in their composition and function. Membrane vesicle functional diversity is staggering: MVs facilitate intercellular communication by delivering quorum signals, genetic information, and small molecules active against a variety of receptors. MVs can deliver destructive virulence factors, alter the composition of the microbiota, take part in the formation of biofilms, assist in the uptake of nutrients, and serve as a chemical waste removal system for bacteria. MVs also facilitate host-microbe interactions including communication. Released in mass, MVs overwhelm the host immune system and injure host tissues; however, there is also evidence that vesicles may take part in processes which promote host health. This review will examine the ascribed functions of MVs within the context of human health and disease.

Keywords: OMV; bacterial membrane vesicles; bacterial nanoparticles; immunity; microbial endocrinology; signaling.

Figure 1

Gram-positive membrane vesicles (MVs; top) form from the cytoplasmic membrane and encapsulate cytoplasmic material. In contrast, Gram-negative MVs (bottom) form primarily from the outer membrane and encapsulate material from the periplasmic compartment; however, contributions from the cytoplasm and cytoplasmic membrane have been reported in Gram-negative species. Mechanisms of MV formation differ and mechanisms of Gram-positive MV formation must overcome an outer layer of peptidoglycan. Gram-negative MVs and Gram-positive MVs carry similar cargos including genetic information, proteins (including toxins and enzymes) as well as small molecule messengers. However, because of evolutionary divergence, specific types of molecules are not shared. For example, LPS and many types of outer membrane proteins are found only in Gram-negative microbes.

Figure 2

Membrane vesicle mediated microbial responses to antibiotic usage. Following exposure to antibiotics, such as the ß-lactam examples used for this figure, many microbes will be induced to activate resistant traits including antibiotic degrading enzymes. MVs made by these bacteria can interfere with the effectiveness of antibiotics through several mechamisms: ß-lactamase containing MVs can directly degrade antibiotics in the surrounding environment, which will protect the host cell and susceptible neighboring cells; (1) ß-lactamase MVs uptaken by related microbial species will confer temporary protection for cells that now carrying the ß-lactamase enzyme without the ß-lactamase gene (2); MVs can carry plasmids encoding for ß-lactamase. Plasmids horizontally transferred to other cells will impart long term genetic immunity in recipient cells as they now produce their own ß-lactamase enzymes. (3) Protective benefits do not always depend on the presence of a protective enzyme. In some cases, antibiotic exposure triggers SOS responses, which result in MV formation through routes like bubbling cell death. This appears to assist bacteria in removing disruptive waste like cellular material damaged by antibiotics. The accumulation of MVs can also contribute to the formation of a biofilm, which can non-specifically shield persister cells and limit the diffusion of antibiotics (4). There are reports of antibiotics triggering the release of virulent MVs (5). In Klebsiella, MVs generated following exposure to imipenem appear to trigger phagocyte pyroptosis and the release of inflammatory mediators (5).

Figure 3

Examples of cross-kingdom signaling involving MVs produced by the gut microbiota. MVs produced by the gut microbiota can act locally, for example, increasing tight junction protein expression in the gut epithelial lining (1). Other MVs can transverse the gut lining where they enter the portal circulation. Most of the MVs that leave the gastrointestinal tract will accumulate in the liver (2). MVs accumulating in these tissues will interact with local dendritic cells, including the Kupffer cells of the liver. Depending on the composition of the MV, this can have a variety of effects. For example, MVs containing indole appear to be anti-inflammatory and appear to protect the liver against steatosis and injury. However, other types of MVs carry MAMPs which can trigger inflammatory responses from the immune system, such as the release of cytokines (3). Some MVs escape hepatic circulation and distribute throughout the rest of the body. Again, depending on the origin and composition of these MVs, differing effects may be observed. MVs from Pseudomonas panacis appear two interfere with the effects of insulin action on adipose tissue (4). In contrast, MVs from Akkermansia muciniphilia appeared to cause positive effects including a loss of body fat. This diagram is only a tiny portion of the full picture.