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IFN-γ fails to overcome inhibition of selected macrophage activation events in response to pathogenic mycobacteria

According to most models of mycobacterial infection, inhibition of the pro-inflammatory macrophage immune responses contributes to the persistence of bacteria. Mycobacterium avium subsp. paratuberculosis (MAP) is a highly successful pathogen in cattle and sheep and is also implicated as the causativ...

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Autores principales: Thirunavukkarasu, Shyamala, Plain, Karren M., Purdie, Auriol C., Whittington, Richard J., de Silva, Kumudika
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432162/
https://www.ncbi.nlm.nih.gov/pubmed/28505170
http://dx.doi.org/10.1371/journal.pone.0176400
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author Thirunavukkarasu, Shyamala
Plain, Karren M.
Purdie, Auriol C.
Whittington, Richard J.
de Silva, Kumudika
author_facet Thirunavukkarasu, Shyamala
Plain, Karren M.
Purdie, Auriol C.
Whittington, Richard J.
de Silva, Kumudika
author_sort Thirunavukkarasu, Shyamala
collection PubMed
description According to most models of mycobacterial infection, inhibition of the pro-inflammatory macrophage immune responses contributes to the persistence of bacteria. Mycobacterium avium subsp. paratuberculosis (MAP) is a highly successful pathogen in cattle and sheep and is also implicated as the causative agent of Crohn’s disease in humans. Pathogenic mycobacteria such as MAP have developed multiple strategies to evade host defence mechanisms including interfering with the macrophages’ capacity to respond to IFN-γ, a feature which might be lacking in non-pathogenic mycobacteria such as M. smegmatis. We hypothesized that pre-sensitisation of macrophages with the pro-inflammatory cytokine IFN-γ would help in overcoming the inhibitory effect of MAP or its antigens on macrophage inflammatory responses. Herein we have compared a series of macrophage activation parameters in response to MAP and M. smegmatis as well as mycobacterial antigens. While IFN-γ did overcome the inhibition in immune suppressive mechanisms in response to MAP antigen as well as M. smegmatis, we could not find a clear role for IFN-γ in overcoming the inhibition of macrophage inflammatory responses to the pathogenic mycobacterium, MAP. We demonstrate that suppression of macrophage defence mechanisms by pathogenic mycobacteria is unlikely to be overcome by prior sensitization with IFN-γ alone. This indicates that IFN-γ signaling pathway-independent mechanisms may exist for overcoming inhibition of macrophage effector functions in response to pathogenic mycobacteria. These findings have important implications in understanding the survival mechanisms of pathogenic mycobacteria directed towards finding better therapeutics and vaccination strategies.
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spelling pubmed-54321622017-05-26 IFN-γ fails to overcome inhibition of selected macrophage activation events in response to pathogenic mycobacteria Thirunavukkarasu, Shyamala Plain, Karren M. Purdie, Auriol C. Whittington, Richard J. de Silva, Kumudika PLoS One Research Article According to most models of mycobacterial infection, inhibition of the pro-inflammatory macrophage immune responses contributes to the persistence of bacteria. Mycobacterium avium subsp. paratuberculosis (MAP) is a highly successful pathogen in cattle and sheep and is also implicated as the causative agent of Crohn’s disease in humans. Pathogenic mycobacteria such as MAP have developed multiple strategies to evade host defence mechanisms including interfering with the macrophages’ capacity to respond to IFN-γ, a feature which might be lacking in non-pathogenic mycobacteria such as M. smegmatis. We hypothesized that pre-sensitisation of macrophages with the pro-inflammatory cytokine IFN-γ would help in overcoming the inhibitory effect of MAP or its antigens on macrophage inflammatory responses. Herein we have compared a series of macrophage activation parameters in response to MAP and M. smegmatis as well as mycobacterial antigens. While IFN-γ did overcome the inhibition in immune suppressive mechanisms in response to MAP antigen as well as M. smegmatis, we could not find a clear role for IFN-γ in overcoming the inhibition of macrophage inflammatory responses to the pathogenic mycobacterium, MAP. We demonstrate that suppression of macrophage defence mechanisms by pathogenic mycobacteria is unlikely to be overcome by prior sensitization with IFN-γ alone. This indicates that IFN-γ signaling pathway-independent mechanisms may exist for overcoming inhibition of macrophage effector functions in response to pathogenic mycobacteria. These findings have important implications in understanding the survival mechanisms of pathogenic mycobacteria directed towards finding better therapeutics and vaccination strategies. Public Library of Science 2017-05-15 /pmc/articles/PMC5432162/ /pubmed/28505170 http://dx.doi.org/10.1371/journal.pone.0176400 Text en © 2017 Thirunavukkarasu 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 (http://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
Thirunavukkarasu, Shyamala
Plain, Karren M.
Purdie, Auriol C.
Whittington, Richard J.
de Silva, Kumudika
IFN-γ fails to overcome inhibition of selected macrophage activation events in response to pathogenic mycobacteria
title IFN-γ fails to overcome inhibition of selected macrophage activation events in response to pathogenic mycobacteria
title_full IFN-γ fails to overcome inhibition of selected macrophage activation events in response to pathogenic mycobacteria
title_fullStr IFN-γ fails to overcome inhibition of selected macrophage activation events in response to pathogenic mycobacteria
title_full_unstemmed IFN-γ fails to overcome inhibition of selected macrophage activation events in response to pathogenic mycobacteria
title_short IFN-γ fails to overcome inhibition of selected macrophage activation events in response to pathogenic mycobacteria
title_sort ifn-γ fails to overcome inhibition of selected macrophage activation events in response to pathogenic mycobacteria
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432162/
https://www.ncbi.nlm.nih.gov/pubmed/28505170
http://dx.doi.org/10.1371/journal.pone.0176400
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