Abstract
Bacteria use a variety of secreted virulence factors to manipulate host cells, thereby causing significant morbidity and mortality. We report a mechanism for the long-distance delivery of multiple bacterial virulence factors, simultaneously and directly into the host cell cytoplasm, thus obviating the need for direct interaction of the pathogen with the host cell to cause cytotoxicity. We show that outer membrane–derived vesicles (OMV) secreted by the opportunistic human pathogen Pseudomonas aeruginosa deliver multiple virulence factors, including β-lactamase, alkaline phosphatase, hemolytic phospholipase C, and Cif, directly into the host cytoplasm via fusion of OMV with lipid rafts in the host plasma membrane. These virulence factors enter the cytoplasm of the host cell via N-WASP–mediated actin trafficking, where they rapidly distribute to specific subcellular locations to affect host cell biology. We propose that secreted virulence factors are not released individually as naked proteins into the surrounding milieu where they may randomly contact the surface of the host cell, but instead bacterial derived OMV deliver multiple virulence factors simultaneously and directly into the host cell cytoplasm in a coordinated manner.
Highlights
Nosocomial infections contribute $4.5 billion to annual healthcare costs in this country alone, with an estimated 2 million nosocomial infections occurring in the US annually, resulting in 99,000 deaths [1]
Outer membrane vesicles deliver toxins to airway epithelial cells Based on reports that multiple virulence factors are packaged in outer membrane vesicles (OMV), we hypothesized that these virulence factors could be
We propose that secreted virulence factors are not released individually as naked proteins into the surrounding milieu where they may randomly contact the surface of the host cell, but instead bacterial-derived outer membrane vesicles (OMV) deliver multiple virulence factors simultaneously and directly into the host cell cytoplasm in a coordinated manner
Summary
Nosocomial infections contribute $4.5 billion to annual healthcare costs in this country alone, with an estimated 2 million nosocomial infections occurring in the US annually, resulting in 99,000 deaths [1]. Beveridge’s group and others have reported that some secreted virulence factors from P. aeruginosa, including b-lactamase, hemolytic phospholipase C, alkaline phosphatase, pro-elastase, hemolysin, and quorum sensing molecules, like N-(3-oxo-dodecanoyl) homoserine lactone and 2-heptyl-3-hydroxy-4-quinolone (PQS) [6,7,13,14], are associated with P. aeruginosa OMV [8,9]. Whether these secreted virulence factors packaged in OMV are eventually delivered to the host and the mechanism by which this occurs is currently unknown. We investigated the possibility that OMV deliver multiple secreted virulence factors into the host cell through a lipid raft-mediated pathway, eliminating the need for intimate contact of the pathogen with the host
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