Mycobacterium tuberculosis canonical virulence factors interfere with a late component of the TLR2 response

For many intracellular pathogens, the phagosome is the site of events and interactions that shape infection outcome. Phagosomal membrane damage, in particular, is proposed to benefit invading pathogens. To define the innate immune consequences of this damage, we profiled macrophage transcriptional r...

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Autores principales:	Amelia E Hinman, Charul Jani, Stephanie C Pringle, Wei R Zhang, Neharika Jain, Amanda J Martinot, Amy K Barczak
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	Mycobacterium tuberculosis tuberculosis TLR2 Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/8c1f5d008f2d40cf98b98547ff9c2bfb
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spelling	oai:doaj.org-article:8c1f5d008f2d40cf98b98547ff9c2bfb2021-11-23T17:17:23ZMycobacterium tuberculosis canonical virulence factors interfere with a late component of the TLR2 response10.7554/eLife.739842050-084Xe73984https://doaj.org/article/8c1f5d008f2d40cf98b98547ff9c2bfb2021-11-01T00:00:00Zhttps://elifesciences.org/articles/73984https://doaj.org/toc/2050-084XFor many intracellular pathogens, the phagosome is the site of events and interactions that shape infection outcome. Phagosomal membrane damage, in particular, is proposed to benefit invading pathogens. To define the innate immune consequences of this damage, we profiled macrophage transcriptional responses to wild-type Mycobacterium tuberculosis (Mtb) and mutants that fail to damage the phagosomal membrane. We identified a set of genes with enhanced expression in response to the mutants. These genes represented a late component of the TLR2-dependent transcriptional response to Mtb, distinct from an earlier component that included Tnf. Expression of the later component was inherent to TLR2 activation, dependent upon endosomal uptake, and enhanced by phagosome acidification. Canonical Mtb virulence factors that contribute to phagosomal membrane damage blunted phagosome acidification and undermined the endosome-specific response. Profiling cell survival and bacterial growth in macrophages demonstrated that the attenuation of these mutants is partially dependent upon TLR2. Further, TLR2 contributed to the attenuated phenotype of one of these mutants in a murine model of infection. These results demonstrate two distinct components of the TLR2 response and identify a component dependent upon endosomal uptake as a point where pathogenic bacteria interfere with the generation of effective inflammation. This interference promotes tuberculosis (TB) pathogenesis in both macrophage and murine infection models.Amelia E HinmanCharul JaniStephanie C PringleWei R ZhangNeharika JainAmanda J MartinotAmy K BarczakeLife Sciences Publications LtdarticleMycobacterium tuberculosistuberculosisTLR2MedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mycobacterium tuberculosis tuberculosis TLR2 Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	Mycobacterium tuberculosis tuberculosis TLR2 Medicine R Science Q Biology (General) QH301-705.5 Amelia E Hinman Charul Jani Stephanie C Pringle Wei R Zhang Neharika Jain Amanda J Martinot Amy K Barczak Mycobacterium tuberculosis canonical virulence factors interfere with a late component of the TLR2 response
description	For many intracellular pathogens, the phagosome is the site of events and interactions that shape infection outcome. Phagosomal membrane damage, in particular, is proposed to benefit invading pathogens. To define the innate immune consequences of this damage, we profiled macrophage transcriptional responses to wild-type Mycobacterium tuberculosis (Mtb) and mutants that fail to damage the phagosomal membrane. We identified a set of genes with enhanced expression in response to the mutants. These genes represented a late component of the TLR2-dependent transcriptional response to Mtb, distinct from an earlier component that included Tnf. Expression of the later component was inherent to TLR2 activation, dependent upon endosomal uptake, and enhanced by phagosome acidification. Canonical Mtb virulence factors that contribute to phagosomal membrane damage blunted phagosome acidification and undermined the endosome-specific response. Profiling cell survival and bacterial growth in macrophages demonstrated that the attenuation of these mutants is partially dependent upon TLR2. Further, TLR2 contributed to the attenuated phenotype of one of these mutants in a murine model of infection. These results demonstrate two distinct components of the TLR2 response and identify a component dependent upon endosomal uptake as a point where pathogenic bacteria interfere with the generation of effective inflammation. This interference promotes tuberculosis (TB) pathogenesis in both macrophage and murine infection models.
format	article
author	Amelia E Hinman Charul Jani Stephanie C Pringle Wei R Zhang Neharika Jain Amanda J Martinot Amy K Barczak
author_facet	Amelia E Hinman Charul Jani Stephanie C Pringle Wei R Zhang Neharika Jain Amanda J Martinot Amy K Barczak
author_sort	Amelia E Hinman
title	Mycobacterium tuberculosis canonical virulence factors interfere with a late component of the TLR2 response
title_short	Mycobacterium tuberculosis canonical virulence factors interfere with a late component of the TLR2 response
title_full	Mycobacterium tuberculosis canonical virulence factors interfere with a late component of the TLR2 response
title_fullStr	Mycobacterium tuberculosis canonical virulence factors interfere with a late component of the TLR2 response
title_full_unstemmed	Mycobacterium tuberculosis canonical virulence factors interfere with a late component of the TLR2 response
title_sort	mycobacterium tuberculosis canonical virulence factors interfere with a late component of the tlr2 response
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/8c1f5d008f2d40cf98b98547ff9c2bfb
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Mycobacterium tuberculosis canonical virulence factors interfere with a late component of the TLR2 response

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