Bacterial Outer Membrane Vesicles and Immune Modulation of the Host

Abstract

This article reviews the role of outer membrane vesicles (OMVs) in mediating the interaction between Gram-negative bacteria and their human hosts. OMVs are produced by a diverse range of Gram-negative bacteria during infection and play a critical role in facilitating host-pathogen interactions without requiring direct cell-to-cell contact. This article describes the mechanisms by which OMVs are formed and subsequently interact with host cells, leading to the transport of microbial protein virulence factors and short interfering RNAs (sRNA) to their host targets, exerting their immunomodulatory effects by targeting specific host signaling pathways. Specifically, this review highlights mechanisms by which OMVs facilitate chronic infection through epigenetic modification of the host immune response. Finally, this review identifies critical knowledge gaps in the field and offers potential avenues for future OMV research, specifically regarding rigor and reproducibility in OMV isolation and characterization methods.

Keywords: DNA methylation (DNAm); immune modulation; inter-kingdom communication; outer membrane vesicles (OMVs).

Figure 1

The explosive cell lysis and budding models of OMV and O-IMV generation. (A) The budding mechanism of OMV generation. Lipoproteins (Lpp) anchor the outer membrane to the peptidoglycan. Membrane proteins and lipopolysaccharides (LPS) decorate the outer membrane and are incorporated into the budding OMV along with periplasmic proteins and sRNA. (B) The budding model of O-IMV generation. Both cytoplasmic and periplasmic proteins and sRNA are incorporated into budding O-IMVs. (C) Cellular stress such as exposure to reactive oxygen species disrupts the membrane of a Gram-negative bacterium, causing membrane fragments to encapsulate free periplasmic and cytoplasmic material and form OMVs and O-IMVs.

Figure 2

Electron microscopy images of OMVs budding from P. aeruginosa. Scale bars indicate 100 nm in panels (A–C) and 500 nm in panel (D). White arrows indicate OMVs in all panels. (A) OMVs budding from P. aeruginosa PAO1 cultured on human bronchial epithelial cells. (B) OMV budding from P. aeruginosa PA14 grown in Minimal Essential Medium (MEM) with 0.4% arginine. (C) OMVs on filamentous structures produced by P. aeruginosa. (D) P. aeruginosa OMV (derived from PAO1 grown in MEM with 10 mM glucose and 8 µM FeCl₃) fusing with a eukaryotic cell. The red arrow indicates a mitochondrion in the airway epithelial cell.

Figure 3

Example of epigenetic regulation of host genes by sRNA delivered by OMV. (1) OMV fuses with a host cell and delivers contents including an sRNA. (2) The sRNA inhibits a methyltransferase, thereby preserving methyl groups on chromosomal DNA. (3) The presence of methyl groups obstructs the binding of transcription factors to promoter regions of immune genes, resulting in reduced expression of immune gene transcripts. Additional epigenetic mechanisms include modulating the expression of DNA methylation modifiers, such as ten-eleven translocation (TET) methylcytosine dioxygenases and DNA methyltransferases (DNMT) [84].