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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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 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.

Detaljer

Författare
  • Wael Bahnan
  • Justin C. Boucher
  • Petoria Gayle
  • Niraj Shrestha
  • Mark Rosen
  • Bertal Aktas
  • Becky Adkins
  • Arba Ager
  • Wasif N. Khan
  • Kurt Schesser
Externa organisationer
  • University of Miami
  • H. Lee Moffitt Cancer Center & Research Institute
  • Janssen Research & Development LLC
  • Brigham and Women's Hospital / Harvard Medical School
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Mikrobiologi inom det medicinska området
  • Immunologi inom det medicinska området

Nyckelord

Originalspråkengelska
Artikelnummere00707-17
TidskriftInfection and Immunity
Volym86
Utgåva nummer3
StatusPublished - 2018 mar 1
PublikationskategoriForskning
Peer review utfördJa
Externt publiceradJa