Inflammasome Activation by Bacterial Outer Membrane Vesicles Requires Guanylate Binding Proteins.
Abstract
The Gram-negative bacterial cell wall component lipopolysaccharide (LPS) is recognized
by the noncanonical inflammasome protein caspase-11 in the cytosol of infected host
cells and thereby prompts an inflammatory immune response linked to sepsis. Host guanylate
binding proteins (GBPs) promote infection-induced caspase-11 activation in tissue
culture models, and yet their in vivo role in LPS-mediated sepsis has remained unexplored.
LPS can be released from lysed bacteria as "free" LPS aggregates or actively secreted
by live bacteria as a component of outer membrane vesicles (OMVs). Here, we report
that GBPs control inflammation and sepsis in mice injected with either free LPS or
purified OMVs derived from Gram-negative Escherichia coli In agreement with our observations
from in vivo experiments, we demonstrate that macrophages lacking GBP2 expression
fail to induce pyroptotic cell death and proinflammatory interleukin-1β (IL-1β) and
IL-18 secretion when exposed to OMVs. We propose that in order to activate caspase-11
in vivo, GBPs control the processing of bacterium-derived OMVs by macrophages as well
as the processing of circulating free LPS by as-yet-undetermined cell types.IMPORTANCE
The bacterial cell wall component LPS is a strong inducer of inflammation and is responsible
for much of the toxicity of Gram-negative bacteria. Bacteria shed some of their cell
wall and its associated LPS in the form of outer membrane vesicles (OMVs). Recent
work demonstrated that secreted OMVs deliver LPS into the host cell cytosol by an
unknown mechanism, resulting in the activation of the proinflammatory LPS sensor caspase-11.
Here, we show that activation of cytosolic caspase-11 by OMVs requires additional
host factors, the so-called guanylate binding proteins (GBPs). The discovery of GBPs
as regulators of OMV-mediated inflammation paves the way toward a mechanistic understanding
of the host response toward bacterial OMVs and may lead to effective strategies to
ameliorate inflammation induced by bacterial infections.
Type
Journal articleSubject
GBP2GBP5
LPS
OMVs
caspase-11
guanylate binding proteins
inflammasome
interferons
lipopolysaccharide
outer membrane vesicles
sepsis
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https://hdl.handle.net/10161/15729Published Version (Please cite this version)
10.1128/mBio.01188-17Publication Info
Finethy, Ryan; Luoma, Sarah; Orench-Rivera, Nichole; Feeley, Eric M; Haldar, Arun
K; Yamamoto, Masahiro; ... Coers, Jörn (2017). Inflammasome Activation by Bacterial Outer Membrane Vesicles Requires Guanylate Binding
Proteins. MBio, 8(5). 10.1128/mBio.01188-17. Retrieved from https://hdl.handle.net/10161/15729.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Jorn Coers
Associate Professor in Molecular Genetics and Microbiology
Bacterial infections remain one of the leading causes of morbidity and mortality worldwide.
The Coers lab seeks to understand fundamental aspects of the innate immune response
to bacterial pathogens as well as the corresponding immune evasion strategies evolved
by human pathogens undermining immunity in order to establish infections. Defining
innate immunity and microbial counter-immunity pathways on a molecular level will
provide roadmaps for the rational design of novel ant
Margarethe Joanna Kuehn
Associate Professor of Biochemistry
Enterotoxigenic E. coli (ETEC) causes traveler's diarrhea and infant mortality in
underdeveloped countries, and Pseudomonas aeruginosa is an opportunistic pathogen
for immunocompromised patients. Like all gram negative bacteria studied to date, ETEC
and P. aeruginosa produce small outer membrane vesicles that can serve as delivery
"bombs" to host tissues. Vesicles contain a subset of outer membrane and
soluble periplasmic proteins and lipids. In tissues and sera of infected hosts,
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