Abstract
Here we show that cells lacking the heme-regulated inhibitor (HRI) are highly resistant to infection by bacterial pathogens. By examining the infection process in wild-type and HRI null cells, we found that HRI is required for pathogens to execute their virulence-associated cellular activities. Specifically, unlike wild-type cells, HRI null cells infected with the gram-negative bacterial pathogen Yersinia are essentially impervious to the cytoskeleton-damaging effects of the Yop virulence factors. This effect is due to reduced functioning of the Yersinia type 3 secretion (T3S) system which injects virulence factors directly into the host cell cytosol. Reduced T3S activity is also observed in HRI null cells infected with the bacterial pathogen Chlamydia which results in a dramatic reduction in its intracellular proliferation. We go on to show that a HRI-mediated process plays a central role in the cellular infection cycle of the Gram-positive pathogen Listeria . For this pathogen, HRI is required for the post-invasion trafficking of the bacterium to the infected host cytosol. Thus by depriving Listeria of its intracellular niche, there is a highly reduced proliferation of Listeria in HRI null cells. We provide evidence that these infection-associated functions of HRI (an eIF2α kinase) are independent of its activity as a regulator of protein synthesis. This is the first report of a host factor whose absence interferes with the function of T3S secretion and cytosolic access by pathogens and makes HRI an excellent target for inhibitors due to its broad virulence-associated activities.
Highlights
Greater knowledge of the mechanisms employed by microbial pathogens to overcome host defenses has allowed for the development of drug-like molecules that target these pathogen virulence-associated structures
In a yeast-based genetic screen using bacterial virulence factors as probes, we found that the stress-induced eIF2 signaling pathway plays a key role in the intracellular activities of both the Yersinia protein kinase A (YpkA) and Yersinia outer protein J (YopJ) [3]
To determine whether this defective inflammatory response of Hri -/- macrophages to LPS reflects a role for heme-regulated inhibitor (HRI) in the cellular response to infection with bacterial pathogens, TNFα expression was measured in Hri +/+ and Hri -/- primary macrophages infected with either Yersinia pseudotuberculosis or Listeria monocytogenes
Summary
Greater knowledge of the mechanisms employed by microbial pathogens to overcome host defenses has allowed for the development of drug-like molecules that target these pathogen virulence-associated structures. It was shown that these compounds inhibit T3SSs of other Gram-negative pathogens such as Chlamydia, Salmonella, and Pseudomonas [2]. We broaden this concept by identifying a host-encoded factor that is required by diverse pathogens to execute their respective cellular infection cycles. In a yeast-based genetic screen using bacterial virulence factors as probes, we found that the stress-induced eIF2 signaling pathway plays a key role in the intracellular activities of both the Yersinia protein kinase A (YpkA) and Yersinia outer protein J (YopJ) [3]. Our studies indicated that in yeast cells YpkA activated eIF2 signaling whereas YopJ, in contrast, negatively regulated eIF2 signaling [3]
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