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Ager, A.
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article
The eIF2α Kinase Heme-Regulated Inhibitor Protects the Host from Infection by Regulating Intracellular Pathogen Trafficking.
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 <i>Listeria monocytogenes</i>, there was reduced translocation of the pathogen to the cytosolic compartment in HRI-deficient cells and consequently reduced loading of pathogen-derived antigens on major histocompatibility complex class I (MHC-I) complexes. Here we show that <i>Hri</i><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 <i>L. monocytogenes</i> infection, there was much greater pathogen proliferation in the liver of <i>Hri</i><sup>-/-</sup> mice than in the liver of <i>Hri</i><sup>+/+</sup> mice. Further, there was a rapid increase of serum interleukin-6 (IL-6) levels in <i>Hri</i><sup>+/+</sup> mice in the first few hours of infection whereas the increase in IL-6 levels in <i>Hri</i><sup>-/-</sup> mice was notably delayed. Consistent with these <i>in vivo</i> findings, the rate of listeriolysin O (LLO)-dependent pathogen efflux from infected <i>Hri</i><sup>-/-</sup> macrophages and fibroblasts was significantly higher than the rate seen with infected <i>Hri</i><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 <i>L. monocytogenes</i> 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.