Pathogenic roles and coping strategies of bacterial outer membrane vesicles in sepsis

Abstract

<p indent="0mm">Sepsis is a life-threatening disease that characterized by systemic inflammatory response and multiple organ dysfunction and mostly caused by Gram-negative bacterial infections. Outer membrane vesicles (OMVs) are multifunctional spherical structures <sc>(10−300 nm)</sc> released from outer membrane of Gram-negative bacteria. Usually, OMVs carry a variety of virulence factors and pathogen-associated molecular patterns (PAMPs), such as toxins, digestive enzymes, lipopolysaccharide (LPS), peptidoglycan, bacterial DNA, etc. Roles of OMVs in bacterial survival include nutrient acquisition, bacterial biofilm formation, antibiotic resistance delivery, and killing of competing microbes. In the pathogenesis of sepsis, OMVs have versatile effects on host cells (such as epithelial cells, immune cells, endothelial cells and platelets, etc.), causing the immune response out of control and the positive feedback loop of inflammation and coagulation formed, which ultimately leading to the systemic inflammatory response and multiple organ dysfunction. Pathogenic effects of OMVs are versatile, including adhesion of host cells, delivery of virulence factors and PAMPs, promotion of inflammatory and immune responses, and facilitation of bacteria survival in the host. Moreover, the main mechanism of bacterial OMVs invading host cells and causing sepsis is related to the recognition of their carried PAMPs with pattern recognition receptors (PRRs) of host cells, including Toll-like receptors (TLRs) on the surface of cell membrane, NOD-like Receptors (NLRs) and cysteinyl aspartate specific proteinases (Caspases) in the cytoplasm. Here, we will briefly introduce the structure composition, biosynthesis and functions of OMVs, particularly focuses on the pathogenic roles of OMVs in the occurrence of sepsis. In addition, the coping strategies of bacterial OMVs in sepsis have been recently investigated since OMVs can carry and transmit a variety of virulence factors. Firstly, OMVs vaccines can prevent the bacterial infection and reduce the OMVs production from the source. Secondly, therapeutic molecules, such as antimicrobial peptides and polymyxin B, can target LPS directly, the common toxic component of bacterial out membranes, and other drugs using TLR4 and Caspase-4/5/11 as targets, also have therapeutic potential to block the inflammatory pathways activated by LPS. Recently, the new drug screening system was established based on bacterial OMVs directly. The treatment effects of the existing drugs for sepsis, including blocking the release of inflammatory factors induced by OMVs, and alleviating the clinical symptoms of sepsis, were reevaluated. Cationic antimicrobial polymers could adsorb the anionic groups of bacterial membrane through the electrostatic interaction, followed by inserting the phospholipid bilayer to destroy the integrity of bacterial membrane and ultimately kill bacteria. Based on the outer membrane structure characteristics of bacterial OMVs (the outmost LPS with more negative charges, toxic protein components, and the inner phospholipid layer with hydrophobicity), the development of cationic antibacterial materials with the integrated function of adsorption and removal of OMVs is feasible to prevent sepsis and other bacterial infection related diseases. Recently, our team designed and synthesized a series of cationic antibacterial polymers, and observed the adsorption capacity of different polymer surfaces to the OMVs of <italic>Pseudomonas aeruginosa</italic> by electron microscopy. The results confirmed that both the cationic polymer membrane and the cation-modified polyurethane foam could adsorb the OMVs. However, the antimicrobial polymers have the possibility to stimulate the release of bacterial OMVs. Therefore, the simultaneous effects of cationic polymers with antimicrobial activities need to be investigated on the release and removal of OMVs in future studies. This review briefly introduces the structural composition, biosynthesis and functions of OMVs, particularly focuses on the pathogenic roles of OMVs in the occurrence of sepsis, and the corresponding coping strategies for the clinical prevention and treatment of sepsis.