title: Bacterial Outer Membrane Vesicles Mediate Cytosolic Localization of LPS and Caspase-11 Activation.
abstract: Sensing of lipopolysaccharide (LPS) in the cytosol triggers caspase-11 activation and is central to host defense against Gram-negative bacterial infections and to the pathogenesis of sepsis. Most Gram-negative bacteria that activate caspase-11, however, are not cytosolic, and the mechanism by which LPS from these bacteria gains access to caspase-11 in the cytosol remains elusive. Here, we identify outer membrane vesicles (OMVs) produced by Gram-negative bacteria as a vehicle that delivers LPS into the cytosol triggering caspase-11-dependent effector responses in vitro and in vivo. OMVs are internalized via endocytosis, and LPS is released into the cytosol from early endosomes. The use of hypovesiculating bacterial mutants, compromised in their ability to generate OMVs, reveals the importance of OMVs in mediating the cytosolic localization of LPS. Collectively, these findings demonstrate a critical role for OMVs in enabling the cytosolic entry of LPS and, consequently, caspase-11 activation during Gram-negative bacterial infections.
authors.affiliation: Department of Immunology, UConn Health School of Medicine, 263 Farmington Avenue, Farmington, CT 06030, USA.
authors.forename: Sivapriya Kailasan
authors.initials: SK
authors.lastname: Vanaja
authors.affiliation: Department of Immunology, UConn Health School of Medicine, 263 Farmington Avenue, Farmington, CT 06030, USA.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Russo
authors.affiliation: Department of Immunology, UConn Health School of Medicine, 263 Farmington Avenue, Farmington, CT 06030, USA.
authors.forename: Bharat
authors.initials: B
authors.lastname: Behl
authors.affiliation: Department of Immunology, UConn Health School of Medicine, 263 Farmington Avenue, Farmington, CT 06030, USA.
authors.forename: Ishita
authors.initials: I
authors.lastname: Banerjee
authors.affiliation: Central Electron Microscopy Facility, UConn Health School of Medicine, 263 Farmington Avenue, Farmington, CT 06030, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Yankova
authors.affiliation: Center for Sepsis Control and Care, Jena University Hospital, Erlanger Allee 101, 07747 Jena, Germany.
authors.forename: Sachin D
authors.initials: SD
authors.lastname: Deshmukh
authors.affiliation: Department of Immunology, UConn Health School of Medicine, 263 Farmington Avenue, Farmington, CT 06030, USA. Electronic address: rathinam@uchc.edu.
authors.forename: Vijay A K
authors.initials: VAK
authors.lastname: Rathinam
mesh_terms: D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D006090:Gram-Negative Bacteria / Q000737:chemistry / Q000166:cytology*; D016905:Gram-Negative Bacterial Infections / Q000276:immunology* / Q000382:microbiology*; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D007375:Interleukin-1 / Q000276:immunology; D008070:Lipopolysaccharides / Q000378:metabolism*; D051379:Mice
chemical_list: D001425:Bacterial Outer Membrane Proteins; D007375:Interleukin-1; D008070:Lipopolysaccharides