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Bacterial Ligands Generated in a Phagosome Are Targets of the Cytosolic Innate Immune System

Macrophages are permissive hosts to intracellular pathogens, but upon activation become microbiocidal effectors of innate and cell-mediated immunity. How the fate of internalized microorganisms is monitored by macrophages, and how that information is integrated to stimulate specific immune responses...

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Detalles Bibliográficos
Autores principales: Herskovits, Anat A, Auerbuch, Victoria, Portnoy, Daniel A
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1839167/
https://www.ncbi.nlm.nih.gov/pubmed/17397264
http://dx.doi.org/10.1371/journal.ppat.0030051
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author Herskovits, Anat A
Auerbuch, Victoria
Portnoy, Daniel A
author_facet Herskovits, Anat A
Auerbuch, Victoria
Portnoy, Daniel A
author_sort Herskovits, Anat A
collection PubMed
description Macrophages are permissive hosts to intracellular pathogens, but upon activation become microbiocidal effectors of innate and cell-mediated immunity. How the fate of internalized microorganisms is monitored by macrophages, and how that information is integrated to stimulate specific immune responses is not understood. Activation of macrophages with interferon (IFN)–γ leads to rapid killing and degradation of Listeria monocytogenes in a phagosome, thus preventing escape of bacteria to the cytosol. Here, we show that activated macrophages induce a specific gene expression program to L. monocytogenes degraded in the phago-lysosome. In addition to activation of Toll-like receptor (TLR) signaling pathways, degraded bacteria also activated a TLR-independent transcriptional response that was similar to the response induced by cytosolic L. monocytogenes. More specifically, degraded bacteria induced a TLR-independent IFN-β response that was previously shown to be specific to cytosolic bacteria and not to intact bacteria localized to the phagosome. This response required the generation of bacterial ligands in the phago-lysosome and was largely dependent on nucleotide-binding oligomerization domain 2 (NOD2), a cytosolic receptor known to respond to bacterial peptidoglycan fragments. The NOD2-dependent response to degraded bacteria required the phagosomal membrane potential and the activity of lysosomal proteases. The NOD2-dependent IFN-β production resulted from synergism with other cytosolic microbial sensors. This study supports the hypothesis that in activated macrophages, cytosolic innate immune receptors are activated by bacterial ligands generated in the phagosome and transported to the cytosol.
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spelling pubmed-18391672007-03-30 Bacterial Ligands Generated in a Phagosome Are Targets of the Cytosolic Innate Immune System Herskovits, Anat A Auerbuch, Victoria Portnoy, Daniel A PLoS Pathog Research Article Macrophages are permissive hosts to intracellular pathogens, but upon activation become microbiocidal effectors of innate and cell-mediated immunity. How the fate of internalized microorganisms is monitored by macrophages, and how that information is integrated to stimulate specific immune responses is not understood. Activation of macrophages with interferon (IFN)–γ leads to rapid killing and degradation of Listeria monocytogenes in a phagosome, thus preventing escape of bacteria to the cytosol. Here, we show that activated macrophages induce a specific gene expression program to L. monocytogenes degraded in the phago-lysosome. In addition to activation of Toll-like receptor (TLR) signaling pathways, degraded bacteria also activated a TLR-independent transcriptional response that was similar to the response induced by cytosolic L. monocytogenes. More specifically, degraded bacteria induced a TLR-independent IFN-β response that was previously shown to be specific to cytosolic bacteria and not to intact bacteria localized to the phagosome. This response required the generation of bacterial ligands in the phago-lysosome and was largely dependent on nucleotide-binding oligomerization domain 2 (NOD2), a cytosolic receptor known to respond to bacterial peptidoglycan fragments. The NOD2-dependent response to degraded bacteria required the phagosomal membrane potential and the activity of lysosomal proteases. The NOD2-dependent IFN-β production resulted from synergism with other cytosolic microbial sensors. This study supports the hypothesis that in activated macrophages, cytosolic innate immune receptors are activated by bacterial ligands generated in the phagosome and transported to the cytosol. Public Library of Science 2007-03 2007-03-30 /pmc/articles/PMC1839167/ /pubmed/17397264 http://dx.doi.org/10.1371/journal.ppat.0030051 Text en © 2007 Herskovits et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Herskovits, Anat A
Auerbuch, Victoria
Portnoy, Daniel A
Bacterial Ligands Generated in a Phagosome Are Targets of the Cytosolic Innate Immune System
title Bacterial Ligands Generated in a Phagosome Are Targets of the Cytosolic Innate Immune System
title_full Bacterial Ligands Generated in a Phagosome Are Targets of the Cytosolic Innate Immune System
title_fullStr Bacterial Ligands Generated in a Phagosome Are Targets of the Cytosolic Innate Immune System
title_full_unstemmed Bacterial Ligands Generated in a Phagosome Are Targets of the Cytosolic Innate Immune System
title_short Bacterial Ligands Generated in a Phagosome Are Targets of the Cytosolic Innate Immune System
title_sort bacterial ligands generated in a phagosome are targets of the cytosolic innate immune system
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1839167/
https://www.ncbi.nlm.nih.gov/pubmed/17397264
http://dx.doi.org/10.1371/journal.ppat.0030051
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