Peptidoglycan Recognition Proteins Kill Bacteria by Inducing Oxidative, Thiol, and Metal Stress

Des Raj Kashyap, Annemarie Rompca, Ahmed Gaballa, John D. Helmann, Jefferson Chan, Christopher J. Chang, Iztok Hozo, Dipika Gupta, Roman Dziarski

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Mammalian Peptidoglycan Recognition Proteins (PGRPs) are a family of evolutionary conserved bactericidal innate immunity proteins, but the mechanism through which they kill bacteria is unclear. We previously proposed that PGRPs are bactericidal due to induction of reactive oxygen species (ROS), a mechanism of killing that was also postulated, and later refuted, for several bactericidal antibiotics. Here, using whole genome expression arrays, qRT-PCR, and biochemical tests we show that in both Escherichia coli and Bacillus subtilis PGRPs induce a transcriptomic signature characteristic of oxidative stress, as well as correlated biochemical changes. However, induction of ROS was required, but not sufficient for PGRP killing. PGRPs also induced depletion of intracellular thiols and increased cytosolic concentrations of zinc and copper, as evidenced by transcriptome changes and supported by direct measurements. Depletion of thiols and elevated concentrations of metals were also required, but by themselves not sufficient, for bacterial killing. Chemical treatment studies demonstrated that efficient bacterial killing can be recapitulated only by the simultaneous addition of agents leading to production of ROS, depletion of thiols, and elevation of intracellular metal concentrations. These results identify a novel mechanism of bacterial killing by innate immunity proteins, which depends on synergistic effect of oxidative, thiol, and metal stress and differs from bacterial killing by antibiotics. These results offer potential targets for developing new antibacterial agents that would kill antibiotic-resistant bacteria.

Original languageEnglish
Article numbere1004280
JournalPLoS Pathogens
Volume10
Issue number7
DOIs
StatePublished - 2014

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Sulfhydryl Compounds
Metals
Bacteria
Anti-Bacterial Agents
Reactive Oxygen Species
Innate Immunity
Bacillus subtilis
Transcriptome
Zinc
Copper
Proteins
Oxidative Stress
peptidoglycan recognition protein
Genome
Escherichia coli
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Peptidoglycan Recognition Proteins Kill Bacteria by Inducing Oxidative, Thiol, and Metal Stress. / Kashyap, Des Raj; Rompca, Annemarie; Gaballa, Ahmed; Helmann, John D.; Chan, Jefferson; Chang, Christopher J.; Hozo, Iztok; Gupta, Dipika; Dziarski, Roman.

In: PLoS Pathogens, Vol. 10, No. 7, e1004280, 2014.

Research output: Contribution to journalArticle

Kashyap, Des Raj ; Rompca, Annemarie ; Gaballa, Ahmed ; Helmann, John D. ; Chan, Jefferson ; Chang, Christopher J. ; Hozo, Iztok ; Gupta, Dipika ; Dziarski, Roman. / Peptidoglycan Recognition Proteins Kill Bacteria by Inducing Oxidative, Thiol, and Metal Stress. In: PLoS Pathogens. 2014 ; Vol. 10, No. 7.
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