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The eIF2α kinase Heme Regulated Inhibitor (HRI) protects the host from infection by regulating intracellular pathogen trafficking

Wael Bahnan, Justin C. Boucher, Petoria Gayle, Niraj Shrestha, Mark Rosen, Bertal Aktas, Becky Adkins, Arba Ager, Wasif N. Khan, Kurt Schesser
doi: https://doi.org/10.1101/142406
Wael Bahnan
1Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida;
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Justin C. Boucher
1Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida;
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Petoria Gayle
1Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida;
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Niraj Shrestha
1Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida;
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Mark Rosen
2Janssen Research & Development, San Diego, California;
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Bertal Aktas
3Hematology Laboratory for Translational Research, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
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Becky Adkins
1Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida;
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Arba Ager
1Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida;
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Wasif N. Khan
1Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida;
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Kurt Schesser
1Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida;
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  • For correspondence: kschesser@med.miami.edu wnkhan@med.miami.edu
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ABSTRACT

Phosphorylation of eIF2α by its kinases is a stress response universally conserved among the eukaryota. Previously, we reported that the eIF2α kinases Heme Regulator Inhibitor (HRI) and Protein Kinase R (PKR) control distinct activities of diverse bacterial pathogens. Specifically for Listeria monocytogenes, it was shown that in HRI-deficient cells there was a reduction in the translocation of the pathogen to the cytosolic compartment as well as reduced loading of pathogen-derived antigens on MHC-1 complexes. Here we show that Hri -/- mice, as well as wild-type mice treated with a HRI inhibitor, are more susceptible to listeriosis. In the first few hours of L. monocytogenes infection, Hri -/- mice supported greater pathogen proliferation in the liver compared to that observed in Hri +/+ mice. This greater susceptibility of Hri -/- mice was not due to deficits in immune cell development as proportions and numbers of innate and adaptive cell compartments were largely normal and these mice could mount potent antibody responses to a model T cell-dependent antigen. Using in vitro cellular infection assays, we show that the rate of pathogen efflux from infected Hri -/- macrophages and fibroblasts is significantly higher than that observed in infected Hri +/+ cells. In contrast to the stark differences between Hri +/+ and Hri -/- cells in the infection dynamics of virulent L. monocytogenes, HRI was entirely dispensable for killing non-virulent strains of L. monocytogenes. These results suggest that in wild-type cells, HRI helps ensure the cellular confinement of virulent L. monocytogenes and loading of cytosolic-derived antigens on MHC-1 complexes that limit pathogen spreading and activating innate immune responses, respectively.

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Posted May 26, 2017.
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The eIF2α kinase Heme Regulated Inhibitor (HRI) protects the host from infection by regulating intracellular pathogen trafficking
Wael Bahnan, Justin C. Boucher, Petoria Gayle, Niraj Shrestha, Mark Rosen, Bertal Aktas, Becky Adkins, Arba Ager, Wasif N. Khan, Kurt Schesser
bioRxiv 142406; doi: https://doi.org/10.1101/142406
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The eIF2α kinase Heme Regulated Inhibitor (HRI) protects the host from infection by regulating intracellular pathogen trafficking
Wael Bahnan, Justin C. Boucher, Petoria Gayle, Niraj Shrestha, Mark Rosen, Bertal Aktas, Becky Adkins, Arba Ager, Wasif N. Khan, Kurt Schesser
bioRxiv 142406; doi: https://doi.org/10.1101/142406

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