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A transcriptomic analysis of the effects of macrophage polarization and endotoxin tolerance on the response to Salmonella

Salmonella is an intracellular pathogen causing significant morbidity and mortality. Its ability to grow inside macrophages is important to virulence, and is dependent on the activation state of the macrophages. Classically activated M1 macrophages are non-permissive for Salmonella growth, while alt...

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Autores principales: Sedivy-Haley, Katharine, Blimkie, Travis, Falsafi, Reza, Lee, Amy Huei-Yi, Hancock, Robert E. W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9565388/
https://www.ncbi.nlm.nih.gov/pubmed/36240188
http://dx.doi.org/10.1371/journal.pone.0276010
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author Sedivy-Haley, Katharine
Blimkie, Travis
Falsafi, Reza
Lee, Amy Huei-Yi
Hancock, Robert E. W.
author_facet Sedivy-Haley, Katharine
Blimkie, Travis
Falsafi, Reza
Lee, Amy Huei-Yi
Hancock, Robert E. W.
author_sort Sedivy-Haley, Katharine
collection PubMed
description Salmonella is an intracellular pathogen causing significant morbidity and mortality. Its ability to grow inside macrophages is important to virulence, and is dependent on the activation state of the macrophages. Classically activated M1 macrophages are non-permissive for Salmonella growth, while alternatively activated M2 macrophages are permissive for Salmonella growth. Here we showed that endotoxin-primed macrophages (M(EP)), such as those associated with sepsis, showed similar levels of Salmonella resistance to M1 macrophages after 2 hr of intracellular infection, but at the 4 hr and 24 hr time points were susceptible like M2 macrophages. To understand this mechanistically, transcriptomic sequencing, RNA-Seq, was performed. This showed that M1 and M(EP) macrophages that had not been exposed to Salmonella, demonstrated a process termed here as primed activation, in expressing relatively higher levels of particular anti-infective genes and pathways, including the JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway. In contrast, in M2 macrophages these genes and pathways were largely expressed only in response to infection. Conversely, in response to infection, M1 macrophages, but not M(EP) macrophages, modulated additional genes known to be associated with susceptibility to Salmonella infection, possibly contributing to the differences in resistance at later time points. Application of the JAK inhibitor Ruxolitinib before infection reduced resistance in M1 macrophages, supporting the importance of early JAK-STAT signalling in M1 resistance to Salmonella.
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spelling pubmed-95653882022-10-15 A transcriptomic analysis of the effects of macrophage polarization and endotoxin tolerance on the response to Salmonella Sedivy-Haley, Katharine Blimkie, Travis Falsafi, Reza Lee, Amy Huei-Yi Hancock, Robert E. W. PLoS One Research Article Salmonella is an intracellular pathogen causing significant morbidity and mortality. Its ability to grow inside macrophages is important to virulence, and is dependent on the activation state of the macrophages. Classically activated M1 macrophages are non-permissive for Salmonella growth, while alternatively activated M2 macrophages are permissive for Salmonella growth. Here we showed that endotoxin-primed macrophages (M(EP)), such as those associated with sepsis, showed similar levels of Salmonella resistance to M1 macrophages after 2 hr of intracellular infection, but at the 4 hr and 24 hr time points were susceptible like M2 macrophages. To understand this mechanistically, transcriptomic sequencing, RNA-Seq, was performed. This showed that M1 and M(EP) macrophages that had not been exposed to Salmonella, demonstrated a process termed here as primed activation, in expressing relatively higher levels of particular anti-infective genes and pathways, including the JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway. In contrast, in M2 macrophages these genes and pathways were largely expressed only in response to infection. Conversely, in response to infection, M1 macrophages, but not M(EP) macrophages, modulated additional genes known to be associated with susceptibility to Salmonella infection, possibly contributing to the differences in resistance at later time points. Application of the JAK inhibitor Ruxolitinib before infection reduced resistance in M1 macrophages, supporting the importance of early JAK-STAT signalling in M1 resistance to Salmonella. Public Library of Science 2022-10-14 /pmc/articles/PMC9565388/ /pubmed/36240188 http://dx.doi.org/10.1371/journal.pone.0276010 Text en © 2022 Sedivy-Haley et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Sedivy-Haley, Katharine
Blimkie, Travis
Falsafi, Reza
Lee, Amy Huei-Yi
Hancock, Robert E. W.
A transcriptomic analysis of the effects of macrophage polarization and endotoxin tolerance on the response to Salmonella
title A transcriptomic analysis of the effects of macrophage polarization and endotoxin tolerance on the response to Salmonella
title_full A transcriptomic analysis of the effects of macrophage polarization and endotoxin tolerance on the response to Salmonella
title_fullStr A transcriptomic analysis of the effects of macrophage polarization and endotoxin tolerance on the response to Salmonella
title_full_unstemmed A transcriptomic analysis of the effects of macrophage polarization and endotoxin tolerance on the response to Salmonella
title_short A transcriptomic analysis of the effects of macrophage polarization and endotoxin tolerance on the response to Salmonella
title_sort transcriptomic analysis of the effects of macrophage polarization and endotoxin tolerance on the response to salmonella
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9565388/
https://www.ncbi.nlm.nih.gov/pubmed/36240188
http://dx.doi.org/10.1371/journal.pone.0276010
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