Detection of Bacterial Membrane Vesicles by NOD-Like Receptors

Abstract

Bacterial membrane vesicles (BMVs) are nanoparticles produced by both Gram-negative and Gram-positive bacteria that can function to modulate immunity in the host. Both outer membrane vesicles (OMVs) and membrane vesicles (MVs), which are released by Gram-negative and Gram-positive bacteria, respectively, contain cargo derived from their parent bacterium, including immune stimulating molecules such as proteins, lipids and nucleic acids. Of these, peptidoglycan (PG) and lipopolysaccharide (LPS) are able to activate host innate immune pattern recognition receptors (PRRs), known as NOD-like receptors (NLRs), such as nucleotide-binding oligomerisation domain-containing protein (NOD) 1, NOD2 and NLRP3. NLR activation is a key driver of inflammation in the host, and BMVs derived from both pathogenic and commensal bacteria have been shown to package PG and LPS in order to modulate the host immune response using NLR-dependent mechanisms. Here, we discuss the packaging of immunostimulatory cargo within OMVs and MVs, their detection by NLRs and the cytokines produced by host cells in response to their detection. Additionally, commensal derived BMVs are thought to shape immunity and contribute to homeostasis in the gut, therefore we also highlight the interactions of commensal derived BMVs with NLRs and their roles in limiting inflammatory diseases.

Keywords: NLRP3; NOD-like receptors (NLRs); NOD1; NOD2; NODs; bacterial membrane vesicles (BMVs); bacterial pathogenesis; inflammasome; membrane vesicles (MVs); outer membrane vesicles (OMVs).

Figure 1

Schematic of a bacterial membrane vesicle. Bacterial membrane vesicles (BMVs), which includes outer membrane vesicles (OMVs) produced by Gram-negative bacteria and membrane vesicles (MVs) produced by Gram-positive bacteria, are nanoparticles produced by all bacteria as part of their normal growth. BMVs contain a range of immunostimulatory microbe-associated molecular patterns (MAMPs) from their parent bacterium, such as peptidoglycan, lipopolysaccharide, DNA and RNA, in addition to bacterial specific virulence determinants such as toxins and enzymes that can mediate the induction of an inflammatory response and promote disease in the host.

Figure 2

Activation of NLRs by BMVs in host cells. BMVs can enter host cells using a number of mechanisms, whereby access to NOD-like receptors (NLRs) occurs. (A) Internalised BMVs interact with NOD1 and NOD2, which can lead to endosomal localisation of NOD1, NF-ĸB activation and the production of proinflammatory cytokines. Furthermore, once intracellular, BMVs can be degraded by the host cellular degradation pathway of autophagy in a NOD1-dependent manner. (B) BMVs can also prime host cells for NLRP3 inflammasome activation, which leads to cleavage of GSDMD, pyroptosis and the production of proinflammatory cytokines. BMVs have also been shown to interact with caspase-11, inducing inflammasome activation and the release of proinflammatory cytokines.