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Author Spotlight: Investigating Bacteriophage-Induced Immune Responses in Gnotobiotic Mice
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An enterococcal phage protein inhibits type IV restriction enzymes involved in antiphage defense

Nathan P Bullen1,2, Cydney N Johnson3, Shelby E Andersen3

  • 1Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4L8, Canada.

Nature Communications
|August 13, 2024
PubMed

Insights

Multidrug-resistant bacteria pose a growing threat. Researchers identified a new phage resistance mechanism in Enterococcus faecalis and discovered a phage inhibitor protein that overcomes this defense.

Area of Science:

  • Microbiology
  • Genetics
  • Molecular Biology

Background:

  • The rise of multidrug-resistant (MDR) bacterial infections, particularly MDR enterococci, is a critical global health concern.
  • Bacteriophage (phage) therapy offers a promising alternative to antibiotics, but bacterial resistance to phages is a significant challenge.
  • Understanding the genetic basis of phage resistance in MDR bacteria is crucial for developing effective phage therapies.

Purpose of the Study:

  • To identify genetic factors conferring phage resistance in *Enterococcus faecalis*.
  • To elucidate the mechanism by which phages overcome bacterial resistance.
  • To characterize a novel phage-inhibitor protein.

Main Methods:

  • Utilized CRISPR interference (CRISPRi) screening to identify phage resistance genes in *Enterococcus faecalis*.
  • Employed genetic and biochemical assays to characterize the function of a identified genetic locus and a restriction enzyme.
  • Investigated phage evolution and the mechanism of a phage-encoded inhibitor protein.

Main Results:

  • Identified a plasmid-borne locus in *Enterococcus faecalis* encoding a Type IV restriction enzyme (TIV-RE) that confers resistance to phage phi47.
  • Demonstrated that phage phi47 evolves to overcome TIV-RE restriction through mutations in a specific inhibitor protein.
  • Characterized the inhibitor, named type IV restriction inhibiting factor A (tifA), which binds and neutralizes diverse TIV-REs.

Conclusions:

  • Discovered a novel phage resistance mechanism mediated by a TIV-RE encoded on a mobilizable plasmid in *Enterococcus faecalis*.
  • Provided mechanistic insights into phage adaptation, highlighting the evolution of inhibitor proteins to overcome bacterial antiphage systems.
  • Advanced the understanding of phage-bacterial interactions in the context of multidrug-resistant pathogens.

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