Inflammasome Activation by Bacterial Outer Membrane Vesicles Requires Guanylate Binding Proteins.

Finethy, Ryan

Luoma, Sarah

Orench-Rivera, Nichole

Feeley, Eric M

Haldar, Arun K

Yamamoto, Masahiro

Kanneganti, Thirumala-Devi

Kuehn, Meta J

Coers, Jörn

Weiss, David S

Rubin, Eric J

United States

2017-11-01T18:34:20Z

2017-11-01T18:34:20Z

2017-10-03

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.

https://www.ncbi.nlm.nih.gov/pubmed/28974614

mBio.01188-17

2150-7511

https://hdl.handle.net/10161/15729

eng

American Society for Microbiology

MBio

10.1128/mBio.01188-17

GBP2

GBP5

LPS

OMVs

caspase-11

guanylate binding proteins

inflammasome

interferons

lipopolysaccharide

outer membrane vesicles

sepsis

Inflammasome Activation by Bacterial Outer Membrane Vesicles Requires Guanylate Binding Proteins.

Journal article

Kuehn, Meta J|0000-0003-0519-3019

Coers, Jörn|0000-0001-8707-4608

https://www.ncbi.nlm.nih.gov/pubmed/28974614

5

Basic Science Departments

Biochemistry

Duke

Duke Cancer Institute

Immunology

Institutes and Centers

Molecular Genetics and Microbiology

School of Medicine

Published online

8