Virulence and immunomodulatory roles of bacterial outer membrane vesicles

Abstract

Outer membrane (OM) vesicles are ubiquitously produced by Gram-negative bacteria during all stages of bacterial growth. OM vesicles are naturally secreted by both pathogenic and nonpathogenic bacteria. Strong experimental evidence exists to categorize OM vesicle production as a type of Gram-negative bacterial virulence factor. A growing body of data demonstrates an association of active virulence factors and toxins with vesicles, suggesting that they play a role in pathogenesis. One of the most popular and best-studied pathogenic functions for membrane vesicles is to serve as natural vehicles for the intercellular transport of virulence factors and other materials directly into host cells. The production of OM vesicles has been identified as an independent bacterial stress response pathway that is activated when bacteria encounter environmental stress, such as what might be experienced during the colonization of host tissues. Their detection in infected human tissues reinforces this theory. Various other virulence factors are also associated with OM vesicles, including adhesins and degradative enzymes. As a result, OM vesicles are heavily laden with pathogen-associated molecular patterns (PAMPs), virulence factors, and other OM components that can impact the course of infection by having toxigenic effects or by the activation of the innate immune response. However, infected hosts can also benefit from OM vesicle production by stimulating their ability to mount an effective defense. Vesicles display antigens and can elicit potent inflammatory and immune responses. In sum, OM vesicles are likely to play a significant role in the virulence of Gram-negative bacterial pathogens.

FIG. 1.

Model of OM vesicle production. Shown is the budding of the Gram-negative bacterial envelope. Released OM vesicles contain periplasmic material and OM proteins and lipids, including PAMPs and other virulence factors, as described in the text. Although details of the mechanism remain unclear, budding is thought to occur in places where lipoprotein links between the OM and the peptidoglycan are broken or missing.

FIG. 2.

Enterotoxigenic E. coli recovered postinfection. Shown are data from scanning electron microscopy of a representative ETEC strain recovered from mouse small intestines 2 h after intragastric inoculation. (Courtesy of Amanda McBroom.)

FIG. 3.

Models of binding, secretion, and vesicle-mediated LT transport into host cells. (A) LT consists of an LTA subunit in a complex with 5 LTB subunits (LTAB₅). LPS and G_M1 both bind in interfaces between subunits of the LTAB₅ complex, but the binding sites are distinct from each other. (B) LT is secreted through the inner membrane by the Sec machinery, folds into the periplasm, is secreted through the outer membrane via GspD of the type 2 secretory system, and binds to LPS on the cell surface via LTB₅. Consequently, vesicles released from the cell have LT on their surface that can act as a tether between G_M1 on the host cell and LPS on the vesicle. Vesicles are internalized by G_M1- and cholesterol-rich microdomains (lipid rafts). Vesicle-associated LT traffics through the Golgi apparatus and ER and is retrograde translocated into the cytosol, where the A1 fragment of LTA is catalytically active. The remaining vesicle material is maintained intracellularly in a nonacidified compartment.