PT  - JOURNAL ARTICLE
AU  - Wael Bahnan
AU  - Justin C. Boucher
AU  - Petoria Gayle
AU  - Niraj Shrestha
AU  - Mark Rosen
AU  - Bertal Aktas
AU  - Becky Adkins
AU  - Arba Ager
AU  - Wasif N. Khan
AU  - Kurt Schesser
TI  - The eIF2α kinase Heme Regulated Inhibitor (HRI) protects the host from infection by regulating intracellular pathogen trafficking
AID  - 10.1101/142406
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 142406
4099  - http://biorxiv.org/content/early/2017/05/25/142406.short
4100  - http://biorxiv.org/content/early/2017/05/25/142406.full
AB  - 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.