The Host-Encoded Heme Regulated Inhibitor (HRI) Facilitates Virulence-Associated Activities of Bacterial Pathogens

Niraj Shrestha, Justin Boucher, Wael Bahnan, Emily S. Clark, Roland Rosqvist, Kenneth A. Fields, Wasif Khan, Kurt Schesser

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Article numbere68754
JournalPLoS One
Volume8
Issue number7
DOIs
StatePublished - Jul 10 2013

Fingerprint

heme
Pathogens
Heme
microbial activity
Virulence
virulence
pathogens
Null Lymphocytes
Listeria
Yersinia
cells
secretion
Virulence Factors
cytosol
infection
Cytosol
Infection
type III secretion system
Chlamydia
cytoskeleton

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

The Host-Encoded Heme Regulated Inhibitor (HRI) Facilitates Virulence-Associated Activities of Bacterial Pathogens. / Shrestha, Niraj; Boucher, Justin; Bahnan, Wael; Clark, Emily S.; Rosqvist, Roland; Fields, Kenneth A.; Khan, Wasif; Schesser, Kurt.

In: PLoS One, Vol. 8, No. 7, e68754, 10.07.2013.

Research output: Contribution to journalArticle

Shrestha, Niraj ; Boucher, Justin ; Bahnan, Wael ; Clark, Emily S. ; Rosqvist, Roland ; Fields, Kenneth A. ; Khan, Wasif ; Schesser, Kurt. / The Host-Encoded Heme Regulated Inhibitor (HRI) Facilitates Virulence-Associated Activities of Bacterial Pathogens. In: PLoS One. 2013 ; Vol. 8, No. 7.
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