Outer Membrane Vesicles Derived from Escherichia coli Induce Systemic Inflammatory Response Syndrome

Abstract

Sepsis, characterized by a systemic inflammatory state that is usually related to Gram-negative bacterial infection, is a leading cause of death worldwide. Although the annual incidence of sepsis is still rising, the exact cause of Gram-negative bacteria-associated sepsis is not clear. Outer membrane vesicles (OMVs), constitutively secreted from Gram-negative bacteria, are nano-sized spherical bilayered proteolipids. Using a mouse model, we showed that intraperitoneal injection of OMVs derived from intestinal Escherichia coli induced lethality. Furthermore, OMVs induced host responses which resemble a clinically relevant condition like sepsis that was characterized by piloerection, eye exudates, hypothermia, tachypnea, leukopenia, disseminated intravascular coagulation, dysfunction of the lungs, hypotension, and systemic induction of tumor necrosis factor-α and interleukin-6. Our study revealed a previously unidentified causative microbial signal in the pathogenesis of sepsis, suggesting OMVs as a new therapeutic target to prevent and/or treat severe sepsis caused by Gram-negative bacterial infection.

Acute experimental Trypanosoma cruzi infection: establishing a murine model that utilises non-invasive measurements of disease parameters

“…One study evaluating the involvement of molecules from Gram-negative bacteria in the promotion of sepsis showed that mice injected with outer membrane vesicles from Escherichia coli presented with clinically relevant symptoms, such as piloerection, eye exudates, hypothermia, tachypnea, leukopenia, hypotension and the systemic induction of tumour necrosis factor-alpha (TNF-α) and interleukin-6 (Park et al 2010). Pro-inflammatory cytokines, especially TNF-α, are associated with the development of cachexia (Silva et al 2001, Porto 2010.…”

Biogenesis of Outer Membrane Vesicles in Serratia marcescens Is Thermoregulated and Can Be Induced by Activation of the Rcs Phosphorelay System

“…Unlike the traditional, highly characterized type I to VI secretion systems, OMVs have the capacity to transport a mixture of soluble and insoluble material, which may be advantageous to the bacteria by protecting their cargo from proteases or by allowing for the assembly of multivalent complexes. Once released from bacteria, the vesicles are free to interact with the host, with considerable evidence that OMVs can be internalized into host cells (9,16,31) and have a role in modulating the host immune response (4,49,54,61).…”

Extracellular Vesicles Derived from Gram-Negative Bacteria, such asEscherichia coli, Induce Emphysema Mainly via IL-17A–Mediated Neutrophilic Inflammation

“…Gram-negative bacteria-derived EVs contain a wide variety of PAMPs, which can be capable of inducing innate immune responses and include LPS, outer membrane lipids, outer membrane proteins, periplasmic proteins, cytoplasmic proteins, DNA, RNA, and other virulence-associated factors (8,27). Our previous study demonstrated that the entry of E. coli EVs into the bloodstream induces systemic inflammation mimicking sepsis (10). In addition, our previous work indicates that EVs in indoor dust are important in the development of neutrophilic inflammation in the lung (11).…”

“…Our previous work has shown that E. coliderived EVs induce systemic inflammation mimicking sepsis after entering the bloodstream (10) and that EVs from indoor dust and also from Staphylococcus aureus can induce neutrophilic pulmonary inflammation (11,12). In the current study, we hypothesized that EVs from Gram-negative bacteria, especially E. coli, are an important cause of neutrophilic inflammation and thereby emphysema in the lung.…”

“…The preparation of EVs from indoor dust and E. coli EVs were isolated from indoor dust and from the culture supernatants of E. coli isolated from the peritoneal lavage fluid of mice with cecal ligation and puncture, as described previously (10,11). Briefly, the dust samples were incubated in PBS for 12 h at 4˚C with stirring and centrifuged twice at 10,000 3 g for 15 min.…”