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ESX-1 exploits type I IFN-signalling to promote a regulatory macrophage phenotype refractory to IFNγ-mediated autophagy and growth restriction of intracellular mycobacteria

Lienard, Julia LU ; Movert, Elin LU ; Valfridsson, Christine LU ; Sturegård, Erik LU and Carlsson, Fredric LU (2016) In Cellular Microbiology 18(10). p.1471-1485
Abstract

Summary: The ability of macrophages to eradicate intracellular pathogens is normally greatly enhanced by IFNγ, a cytokine produced mainly after onset of adaptive immunity. However, adaptive immunity is unable to provide sterilizing immunity against mycobacteria, suggesting that mycobacteria have evolved virulence strategies to inhibit the bactericidal effect of IFNγ-signalling in macrophages. Still, the host-pathogen interactions and cellular mechanisms responsible for this feature have remained elusive. We demonstrate that the ESX-1 type VII secretion systems of Mycobacterium tuberculosis and Mycobacteriummarinum exploit type I IFN-signalling to promote an IL-12low/IL-10high regulatory macrophage phenotype... (More)

Summary: The ability of macrophages to eradicate intracellular pathogens is normally greatly enhanced by IFNγ, a cytokine produced mainly after onset of adaptive immunity. However, adaptive immunity is unable to provide sterilizing immunity against mycobacteria, suggesting that mycobacteria have evolved virulence strategies to inhibit the bactericidal effect of IFNγ-signalling in macrophages. Still, the host-pathogen interactions and cellular mechanisms responsible for this feature have remained elusive. We demonstrate that the ESX-1 type VII secretion systems of Mycobacterium tuberculosis and Mycobacteriummarinum exploit type I IFN-signalling to promote an IL-12low/IL-10high regulatory macrophage phenotype characterized by secretion of IL-10, IL-27 and IL-6. This mechanism had no impact on intracellular growth in the absence of IFNγ but suppressed IFNγ-mediated autophagy and growth restriction, indicating that the regulatory phenotype extends to function. The IFNγ-refractory phenotype was partly mediated by IL-27-signalling, establishing functional relevance for this downstream cytokine. These findings identify a novel macrophage-modulating function for the ESX-1 secretion system that may contribute to suppress the efficacy of adaptive immunity and provide mechanistic insight into the antagonistic cross talk between type I IFNs and IFNγ in mycobacterial infection.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cellular Microbiology
volume
18
issue
10
pages
15 pages
publisher
Wiley-Blackwell
external identifiers
  • Scopus:84963859109
  • Scopus:84987804413
ISSN
1462-5814
DOI
10.1111/cmi.12594
language
English
LU publication?
yes
id
5bc40f21-5c7c-44e2-9f8d-0ee7d8a6d7ac
date added to LUP
2016-07-08 08:56:09
date last changed
2016-10-27 09:07:21
@misc{5bc40f21-5c7c-44e2-9f8d-0ee7d8a6d7ac,
  abstract     = {<p>Summary: The ability of macrophages to eradicate intracellular pathogens is normally greatly enhanced by IFNγ, a cytokine produced mainly after onset of adaptive immunity. However, adaptive immunity is unable to provide sterilizing immunity against mycobacteria, suggesting that mycobacteria have evolved virulence strategies to inhibit the bactericidal effect of IFNγ-signalling in macrophages. Still, the host-pathogen interactions and cellular mechanisms responsible for this feature have remained elusive. We demonstrate that the ESX-1 type VII secretion systems of Mycobacterium tuberculosis and Mycobacteriummarinum exploit type I IFN-signalling to promote an IL-12<sup>low</sup>/IL-10<sup>high</sup> regulatory macrophage phenotype characterized by secretion of IL-10, IL-27 and IL-6. This mechanism had no impact on intracellular growth in the absence of IFNγ but suppressed IFNγ-mediated autophagy and growth restriction, indicating that the regulatory phenotype extends to function. The IFNγ-refractory phenotype was partly mediated by IL-27-signalling, establishing functional relevance for this downstream cytokine. These findings identify a novel macrophage-modulating function for the ESX-1 secretion system that may contribute to suppress the efficacy of adaptive immunity and provide mechanistic insight into the antagonistic cross talk between type I IFNs and IFNγ in mycobacterial infection.</p>},
  author       = {Lienard, Julia and Movert, Elin and Valfridsson, Christine and Sturegård, Erik and Carlsson, Fredric},
  issn         = {1462-5814},
  language     = {eng},
  number       = {10},
  pages        = {1471--1485},
  publisher    = {ARRAY(0x87d0178)},
  series       = {Cellular Microbiology},
  title        = {ESX-1 exploits type I IFN-signalling to promote a regulatory macrophage phenotype refractory to IFNγ-mediated autophagy and growth restriction of intracellular mycobacteria},
  url          = {http://dx.doi.org/10.1111/cmi.12594},
  volume       = {18},
  year         = {2016},
}