using-bacterial-pathogen-to-probe-for-cellular-organismic-level-host

Using a Bacterial Pathogen to Probe for Cellular and Organismic-level Host Responses

There are a variety of strategies bacterial pathogens employ to survive and proliferate once inside the eukaryotic cell. The so-called 'cytosolic' ...

University of Miami

University of Miami Miller School of Medicine

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 , 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  mice, as well as wild-type mice treated with an HRI inhibitor, are more susceptible to listeriosis. In the first few hours of  infection, there was much greater pathogen proliferation in the liver of  mice than in the liver of  mice. Further, there was a rapid increase of serum interleukin-6 (IL-6) levels in  mice in the first few hours of infection whereas the increase in IL-6 levels in  mice was notably delayed. Consistent with these  findings, the rate of listeriolysin O (LLO)-dependent pathogen efflux from infected  macrophages and fibroblasts was significantly higher than the rate seen with infected  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  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.

Petoria Gayle

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