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The eIF2α Kinase Heme-Regulated Inhibitor Protects the Host from Infection by Regulating Intracellular Pathogen
Wael Bahnan1, Justin C Boucher1, Petoria Gayle1
1Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA.
Infection and Immunity
|January 10, 2018
Summary
The heme-regulated inhibitor (HRI) kinase limits bacterial infection by controlling pathogen spread and promoting immune signaling. HRI deficiency increases susceptibility to Listeria monocytogenes, highlighting its critical role in host defense.
Area of Science:
- Immunology
- Cell Biology
- Microbiology
Background:
- Host immune responses involve cell-autonomous and system-level mechanisms to control pathogen replication.
- Eukaryotic initiation factor 2α (eIF2α) kinases, including heme-regulated inhibitor (HRI) and protein kinase R (PKR), regulate cellular and immune activities against bacterial pathogens.
- Previous studies showed HRI deficiency reduces Listeria monocytogenes translocation and MHC-I antigen loading.
Purpose of the Study:
- To investigate the role of HRI in host defense against Listeria monocytogenes infection in vivo and in vitro.
- To determine the impact of HRI deficiency on pathogen proliferation, immune cell responses, and pathogen containment.
Main Methods:
- Utilized HRI-deficient (Hri-/-) and wild-type (Hri+/+) mice for listeriosis studies.
- Administered an HRI inhibitor to wild-type mice to assess its effect on infection.
- Quantified pathogen proliferation in the liver, measured serum interleukin-6 (IL-6) levels, and assessed pathogen efflux from infected macrophages and fibroblasts.
- Treated cells with an eIF2α kinase activator to evaluate its impact on infection phenotypes.
Main Results:
- Hri-/- mice and mice treated with an HRI inhibitor exhibited increased susceptibility to listeriosis.
- Greater Listeria monocytogenes proliferation was observed in the livers of Hri-/- mice compared to Hri+/+ mice.
- Serum IL-6 levels increased rapidly in Hri+/+ mice but showed a delayed increase in Hri-/- mice during early infection.
- Pathogen efflux from Hri-/- macrophages and fibroblasts was significantly higher than in Hri+/+ cells.
- Activation of eIF2α kinases enhanced both HRI- and PKR-dependent infection phenotypes.
Conclusions:
- HRI plays a crucial role in the cellular confinement and killing of virulent Listeria monocytogenes.
- HRI promotes a system-level cytokine response, essential for limiting pathogen replication in the early hours of infection.
- The HRI signaling pathway is pharmacologically malleable, suggesting potential therapeutic targets.
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