Guanylate-Binding Protein-Dependent Noncanonical Inflammasome Activation Prevents <named-content content-type="genus-species">Burkholderia thailandensis</named-content>-Induced Multinucleated Giant Cell Formation

ABSTRACT Inflammasomes are cytosolic multiprotein signaling complexes that are activated upon pattern recognition receptor-mediated recognition of pathogen-derived ligands or endogenous danger signals. Their assembly activates the downstream inflammatory caspase-1 and caspase-4/5 (human) or caspase-...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Marisa Dilucca, Saray Ramos, Kateryna Shkarina, José Carlos Santos, Petr Broz
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	antimicrobial mechanisms guanylate-binding proteins host-pathogen interactions inflammasomes innate immunity Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/02bb376013384fafb53039e535537444
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:02bb376013384fafb53039e535537444
record_format	dspace
spelling	oai:doaj.org-article:02bb376013384fafb53039e5355374442021-11-10T18:37:52ZGuanylate-Binding Protein-Dependent Noncanonical Inflammasome Activation Prevents <named-content content-type="genus-species">Burkholderia thailandensis</named-content>-Induced Multinucleated Giant Cell Formation10.1128/mBio.02054-212150-7511https://doaj.org/article/02bb376013384fafb53039e5355374442021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02054-21https://doaj.org/toc/2150-7511ABSTRACT Inflammasomes are cytosolic multiprotein signaling complexes that are activated upon pattern recognition receptor-mediated recognition of pathogen-derived ligands or endogenous danger signals. Their assembly activates the downstream inflammatory caspase-1 and caspase-4/5 (human) or caspase-11 (mouse), which induces cytokine release and pyroptotic cell death through the cleavage of the pore-forming effector gasdermin D. Pathogen detection by host cells also results in the production and release of interferons (IFNs), which fine-tune inflammasome-mediated responses. IFN-induced guanylate-binding proteins (GBPs) have been shown to control the activation of the noncanonical inflammasome by recruiting caspase-4 on the surface of cytosolic Gram-negative bacteria and promoting its interaction with lipopolysaccharide (LPS). The Gram-negative opportunistic bacterial pathogen Burkholderia thailandensis infects epithelial cells and macrophages and hijacks the host actin polymerization machinery to spread into neighboring cells. This process causes host cell fusion and the formation of so-called multinucleated giant cells (MNGCs). Caspase-1- and IFN-regulated caspase-11-mediated inflammasome pathways play an important protective role against B. thailandensis in mice, but little is known about the role of IFNs and inflammasomes during B. thailandensis infection of human cells, particularly epithelial cells. Here, we report that IFN-γ priming of human epithelial cells restricts B. thailandensis-induced MNGC formation in a GBP1-dependent manner. Mechanistically, GBP1 does not promote bacteriolysis or impair actin-based bacterial motility but acts by inducing caspase-4-dependent pyroptosis of the infected cell. In addition, we show that IFN-γ priming of human primary macrophages confers a more efficient antimicrobial effect through inflammasome activation, further confirming the important role that interferon signaling plays in restricting Burkholderia replication and spread. IMPORTANCE The Gram-negative bacteria of the Burkholderia species are associated with human diseases ranging from pneumonia to life-threatening melioidosis. Upon infection through inhalation, ingestion, or the percutaneous route, these bacteria can spread and establish granuloma-like lesions resulting from the fusion of host cells to form multinucleated giant cells (MNGCs). Burkholderia resistance to several antibiotics highlights the importance to better understand how the innate immune system controls infections. Here, we report that interferons protect human epithelial cells against Burkholderia-induced MNGC formation, specifically through the action of the interferon-induced GBP1 protein. Mechanistically, GBP1 acts by inducing caspase-4-dependent cell death through pyroptosis, allowing the infected cells to be quickly eliminated before bacterial spread and the formation of MNGCs. This study provides evidence that interferon-induced innate immune activation, through GBP1 and caspase-4, confers protection against Burkholderia infection, potentially opening new perspectives for therapeutic approaches.Marisa DiluccaSaray RamosKateryna ShkarinaJosé Carlos SantosPetr BrozAmerican Society for Microbiologyarticleantimicrobial mechanismsguanylate-binding proteinshost-pathogen interactionsinflammasomesinnate immunityMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	antimicrobial mechanisms guanylate-binding proteins host-pathogen interactions inflammasomes innate immunity Microbiology QR1-502
spellingShingle	antimicrobial mechanisms guanylate-binding proteins host-pathogen interactions inflammasomes innate immunity Microbiology QR1-502 Marisa Dilucca Saray Ramos Kateryna Shkarina José Carlos Santos Petr Broz Guanylate-Binding Protein-Dependent Noncanonical Inflammasome Activation Prevents <named-content content-type="genus-species">Burkholderia thailandensis</named-content>-Induced Multinucleated Giant Cell Formation
description	ABSTRACT Inflammasomes are cytosolic multiprotein signaling complexes that are activated upon pattern recognition receptor-mediated recognition of pathogen-derived ligands or endogenous danger signals. Their assembly activates the downstream inflammatory caspase-1 and caspase-4/5 (human) or caspase-11 (mouse), which induces cytokine release and pyroptotic cell death through the cleavage of the pore-forming effector gasdermin D. Pathogen detection by host cells also results in the production and release of interferons (IFNs), which fine-tune inflammasome-mediated responses. IFN-induced guanylate-binding proteins (GBPs) have been shown to control the activation of the noncanonical inflammasome by recruiting caspase-4 on the surface of cytosolic Gram-negative bacteria and promoting its interaction with lipopolysaccharide (LPS). The Gram-negative opportunistic bacterial pathogen Burkholderia thailandensis infects epithelial cells and macrophages and hijacks the host actin polymerization machinery to spread into neighboring cells. This process causes host cell fusion and the formation of so-called multinucleated giant cells (MNGCs). Caspase-1- and IFN-regulated caspase-11-mediated inflammasome pathways play an important protective role against B. thailandensis in mice, but little is known about the role of IFNs and inflammasomes during B. thailandensis infection of human cells, particularly epithelial cells. Here, we report that IFN-γ priming of human epithelial cells restricts B. thailandensis-induced MNGC formation in a GBP1-dependent manner. Mechanistically, GBP1 does not promote bacteriolysis or impair actin-based bacterial motility but acts by inducing caspase-4-dependent pyroptosis of the infected cell. In addition, we show that IFN-γ priming of human primary macrophages confers a more efficient antimicrobial effect through inflammasome activation, further confirming the important role that interferon signaling plays in restricting Burkholderia replication and spread. IMPORTANCE The Gram-negative bacteria of the Burkholderia species are associated with human diseases ranging from pneumonia to life-threatening melioidosis. Upon infection through inhalation, ingestion, or the percutaneous route, these bacteria can spread and establish granuloma-like lesions resulting from the fusion of host cells to form multinucleated giant cells (MNGCs). Burkholderia resistance to several antibiotics highlights the importance to better understand how the innate immune system controls infections. Here, we report that interferons protect human epithelial cells against Burkholderia-induced MNGC formation, specifically through the action of the interferon-induced GBP1 protein. Mechanistically, GBP1 acts by inducing caspase-4-dependent cell death through pyroptosis, allowing the infected cells to be quickly eliminated before bacterial spread and the formation of MNGCs. This study provides evidence that interferon-induced innate immune activation, through GBP1 and caspase-4, confers protection against Burkholderia infection, potentially opening new perspectives for therapeutic approaches.
format	article
author	Marisa Dilucca Saray Ramos Kateryna Shkarina José Carlos Santos Petr Broz
author_facet	Marisa Dilucca Saray Ramos Kateryna Shkarina José Carlos Santos Petr Broz
author_sort	Marisa Dilucca
title	Guanylate-Binding Protein-Dependent Noncanonical Inflammasome Activation Prevents <named-content content-type="genus-species">Burkholderia thailandensis</named-content>-Induced Multinucleated Giant Cell Formation
title_short	Guanylate-Binding Protein-Dependent Noncanonical Inflammasome Activation Prevents <named-content content-type="genus-species">Burkholderia thailandensis</named-content>-Induced Multinucleated Giant Cell Formation
title_full	Guanylate-Binding Protein-Dependent Noncanonical Inflammasome Activation Prevents <named-content content-type="genus-species">Burkholderia thailandensis</named-content>-Induced Multinucleated Giant Cell Formation
title_fullStr	Guanylate-Binding Protein-Dependent Noncanonical Inflammasome Activation Prevents <named-content content-type="genus-species">Burkholderia thailandensis</named-content>-Induced Multinucleated Giant Cell Formation
title_full_unstemmed	Guanylate-Binding Protein-Dependent Noncanonical Inflammasome Activation Prevents <named-content content-type="genus-species">Burkholderia thailandensis</named-content>-Induced Multinucleated Giant Cell Formation
title_sort	guanylate-binding protein-dependent noncanonical inflammasome activation prevents <named-content content-type="genus-species">burkholderia thailandensis</named-content>-induced multinucleated giant cell formation
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/02bb376013384fafb53039e535537444
work_keys_str_mv	AT marisadilucca guanylatebindingproteindependentnoncanonicalinflammasomeactivationpreventsnamedcontentcontenttypegenusspeciesburkholderiathailandensisnamedcontentinducedmultinucleatedgiantcellformation AT sarayramos guanylatebindingproteindependentnoncanonicalinflammasomeactivationpreventsnamedcontentcontenttypegenusspeciesburkholderiathailandensisnamedcontentinducedmultinucleatedgiantcellformation AT katerynashkarina guanylatebindingproteindependentnoncanonicalinflammasomeactivationpreventsnamedcontentcontenttypegenusspeciesburkholderiathailandensisnamedcontentinducedmultinucleatedgiantcellformation AT josecarlossantos guanylatebindingproteindependentnoncanonicalinflammasomeactivationpreventsnamedcontentcontenttypegenusspeciesburkholderiathailandensisnamedcontentinducedmultinucleatedgiantcellformation AT petrbroz guanylatebindingproteindependentnoncanonicalinflammasomeactivationpreventsnamedcontentcontenttypegenusspeciesburkholderiathailandensisnamedcontentinducedmultinucleatedgiantcellformation
_version_	1718439741951574016

Guanylate-Binding Protein-Dependent Noncanonical Inflammasome Activation Prevents <named-content content-type="genus-species">Burkholderia thailandensis</named-content>-Induced Multinucleated Giant Cell Formation

Ejemplares similares