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) promo...

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Autores principales:	Ryan Finethy, Sarah Luoma, Nichole Orench-Rivera, Eric M. Feeley, Arun K. Haldar, Masahiro Yamamoto, Thirumala-Devi Kanneganti, Meta J. Kuehn, Jörn Coers
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	GBP2 GBP5 LPS OMVs caspase-11 guanylate binding proteins Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/bb4d0719860949808c96af8cd370889b
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spelling	oai:doaj.org-article:bb4d0719860949808c96af8cd370889b2021-11-15T15:51:50ZInflammasome Activation by Bacterial Outer Membrane Vesicles Requires Guanylate Binding Proteins10.1128/mBio.01188-172150-7511https://doaj.org/article/bb4d0719860949808c96af8cd370889b2017-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01188-17https://doaj.org/toc/2150-7511ABSTRACT 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.Ryan FinethySarah LuomaNichole Orench-RiveraEric M. FeeleyArun K. HaldarMasahiro YamamotoThirumala-Devi KannegantiMeta J. KuehnJörn CoersAmerican Society for MicrobiologyarticleGBP2GBP5LPSOMVscaspase-11guanylate binding proteinsMicrobiologyQR1-502ENmBio, Vol 8, Iss 5 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	GBP2 GBP5 LPS OMVs caspase-11 guanylate binding proteins Microbiology QR1-502
spellingShingle	GBP2 GBP5 LPS OMVs caspase-11 guanylate binding proteins Microbiology QR1-502 Ryan Finethy Sarah Luoma Nichole Orench-Rivera Eric M. Feeley Arun K. Haldar Masahiro Yamamoto Thirumala-Devi Kanneganti Meta J. Kuehn Jörn Coers Inflammasome Activation by Bacterial Outer Membrane Vesicles Requires Guanylate Binding Proteins
description	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.
format	article
author	Ryan Finethy Sarah Luoma Nichole Orench-Rivera Eric M. Feeley Arun K. Haldar Masahiro Yamamoto Thirumala-Devi Kanneganti Meta J. Kuehn Jörn Coers
author_facet	Ryan Finethy Sarah Luoma Nichole Orench-Rivera Eric M. Feeley Arun K. Haldar Masahiro Yamamoto Thirumala-Devi Kanneganti Meta J. Kuehn Jörn Coers
author_sort	Ryan Finethy
title	Inflammasome Activation by Bacterial Outer Membrane Vesicles Requires Guanylate Binding Proteins
title_short	Inflammasome Activation by Bacterial Outer Membrane Vesicles Requires Guanylate Binding Proteins
title_full	Inflammasome Activation by Bacterial Outer Membrane Vesicles Requires Guanylate Binding Proteins
title_fullStr	Inflammasome Activation by Bacterial Outer Membrane Vesicles Requires Guanylate Binding Proteins
title_full_unstemmed	Inflammasome Activation by Bacterial Outer Membrane Vesicles Requires Guanylate Binding Proteins
title_sort	inflammasome activation by bacterial outer membrane vesicles requires guanylate binding proteins
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/bb4d0719860949808c96af8cd370889b
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Inflammasome Activation by Bacterial Outer Membrane Vesicles Requires Guanylate Binding Proteins

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