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The eIF2α kinase heme-regulated inhibitor protects the host from infection by regulating intracellular pathogen trafficking

Bahnan, Wael LU ; Boucher, Justin C. ; Gayle, Petoria ; Shrestha, Niraj ; Rosen, Mark ; Aktas, Bertal ; Adkins, Becky ; Ager, Arba ; Khan, Wasif N. and Schesser, Kurt (2018) In Infection and Immunity 86(3).
Abstract

The host employs both cell-autonomous and system-level responses to limit pathogen replication in the initial stages of infection. Previously, we reported that the eukaryotic initiation factor 2α (eIF2α) kinases heme-regulated inhibitor (HRI) and protein kinase R (PKR) control distinct cellular and immune-related activities in response to diverse bacterial pathogens. Specifically for Listeria monocytogenes, there was reduced translocation of the pathogen to the cytosolic compartment in HRIdeficient cells and consequently reduced loading of pathogen-derived antigens on major histocompatibility complex class I (MHC-I) complexes. Here we show that Hri-/- mice, as well as wild-type mice treated with an HRI inhibitor, are more... (More)

The host employs both cell-autonomous and system-level responses to limit pathogen replication in the initial stages of infection. Previously, we reported that the eukaryotic initiation factor 2α (eIF2α) kinases heme-regulated inhibitor (HRI) and protein kinase R (PKR) control distinct cellular and immune-related activities in response to diverse bacterial pathogens. Specifically for Listeria monocytogenes, there was reduced translocation of the pathogen to the cytosolic compartment in HRIdeficient cells and consequently reduced loading of pathogen-derived antigens on major histocompatibility complex class I (MHC-I) complexes. Here we show that Hri-/- mice, as well as wild-type mice treated with an HRI inhibitor, are more susceptible to listeriosis. In the first few hours of L. monocytogenes infection, there was much greater pathogen proliferation in the liver of Hri-/- mice than in the liver of Hri+/+ mice. Further, there was a rapid increase of serum interleukin-6 (IL-6) levels in Hri+/+ mice in the first few hours of infection whereas the increase in IL-6 levels in Hri-/- mice was notably delayed. Consistent with these in vivo findings, the rate of listeriolysin O (LLO)-dependent pathogen efflux from infected Hri-/- macrophages and fibroblasts was significantly higher than the rate seen with infected Hri+/+ cells. Treatment of cells with an eIF2α kinase activator enhanced both the HRI-dependent and PKR-dependent infection phenotypes, further indicating the pharmacologically malleability of this signaling pathway. Collectively, these results suggest that HRI mediates the cellular confinement and killing of virulent L. monocytogenes in addition to promoting a system-level cytokine response and that both are required to limit pathogen replication during the first few hours of infection.

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author
; ; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
EIF2α kinase, Heme-regulated inhibitor, HRI, Listeria monocytogenes, Macrophages, Microbial pathogenesis, Stress response
in
Infection and Immunity
volume
86
issue
3
article number
e00707-17
publisher
American Society for Microbiology
external identifiers
  • pmid:29311243
  • scopus:85042300494
ISSN
0019-9567
DOI
10.1128/IAI.00707-17
language
English
LU publication?
no
id
0d4ca3c2-fada-4f68-812c-39188c774e27
date added to LUP
2018-03-17 19:48:12
date last changed
2024-02-13 17:12:56
@article{0d4ca3c2-fada-4f68-812c-39188c774e27,
  abstract     = {{<p>The host employs both cell-autonomous and system-level responses to limit pathogen replication in the initial stages of infection. Previously, we reported that the eukaryotic initiation factor 2α (eIF2α) kinases heme-regulated inhibitor (HRI) and protein kinase R (PKR) control distinct cellular and immune-related activities in response to diverse bacterial pathogens. Specifically for Listeria monocytogenes, there was reduced translocation of the pathogen to the cytosolic compartment in HRIdeficient cells and consequently reduced loading of pathogen-derived antigens on major histocompatibility complex class I (MHC-I) complexes. Here we show that Hri<sup>-/-</sup> mice, as well as wild-type mice treated with an HRI inhibitor, are more susceptible to listeriosis. In the first few hours of L. monocytogenes infection, there was much greater pathogen proliferation in the liver of Hri<sup>-/-</sup> mice than in the liver of Hri<sup>+/+</sup> mice. Further, there was a rapid increase of serum interleukin-6 (IL-6) levels in Hri<sup>+/+</sup> mice in the first few hours of infection whereas the increase in IL-6 levels in Hri<sup>-/-</sup> mice was notably delayed. Consistent with these in vivo findings, the rate of listeriolysin O (LLO)-dependent pathogen efflux from infected Hri<sup>-/-</sup> macrophages and fibroblasts was significantly higher than the rate seen with infected Hri<sup>+/+</sup> cells. Treatment of cells with an eIF2α kinase activator enhanced both the HRI-dependent and PKR-dependent infection phenotypes, further indicating the pharmacologically malleability of this signaling pathway. Collectively, these results suggest that HRI mediates the cellular confinement and killing of virulent L. monocytogenes in addition to promoting a system-level cytokine response and that both are required to limit pathogen replication during the first few hours of infection.</p>}},
  author       = {{Bahnan, Wael and Boucher, Justin C. and Gayle, Petoria and Shrestha, Niraj and Rosen, Mark and Aktas, Bertal and Adkins, Becky and Ager, Arba and Khan, Wasif N. and Schesser, Kurt}},
  issn         = {{0019-9567}},
  keywords     = {{EIF2α kinase; Heme-regulated inhibitor; HRI; Listeria monocytogenes; Macrophages; Microbial pathogenesis; Stress response}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{3}},
  publisher    = {{American Society for Microbiology}},
  series       = {{Infection and Immunity}},
  title        = {{The eIF2α kinase heme-regulated inhibitor protects the host from infection by regulating intracellular pathogen trafficking}},
  url          = {{http://dx.doi.org/10.1128/IAI.00707-17}},
  doi          = {{10.1128/IAI.00707-17}},
  volume       = {{86}},
  year         = {{2018}},
}