Type I CRISPR-Cas targets endogenous genes and regulates virulence to evade mammalian host immunity

Cell Res. 2016 Dec;26(12):1273-1287. doi: 10.1038/cr.2016.135. Epub 2016 Nov 18.

Abstract

Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) systems in bacteria and archaea provide adaptive immunity against invading foreign nucleic acids. Previous studies suggest that certain bacteria employ their Type II CRISPR-Cas systems to target their own genes, thus evading host immunity. However, whether other CRISPR-Cas systems have similar functions during bacterial invasion of host cells remains unknown. Here we identify a novel role for Type I CRISPR-Cas systems in evading host defenses in Pseudomonas aeruginosa strain UCBPP-PA14. The Type I CRISPR-Cas system of PA14 targets the mRNA of the bacterial quorum-sensing regulator LasR to dampen the recognition by toll-like receptor 4, thus diminishing the pro-inflammatory responses of the host in cell and mouse models. Mechanistically, this nuclease-mediated RNA degradation requires a "5'-GGN-3'" recognition motif in the target mRNA, and HD and DExD/H domains in Cas3 of the Type I CRISPR-Cas system. As LasR and Type I CRISPR-Cas systems are ubiquitously present in bacteria, our findings elucidate an important common mechanism underlying bacterial virulence.

MeSH terms

  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Base Sequence
  • Bronchoalveolar Lavage Fluid / chemistry
  • Bronchoalveolar Lavage Fluid / cytology
  • CRISPR-Associated Proteins / chemistry
  • CRISPR-Associated Proteins / genetics
  • CRISPR-Cas Systems / genetics*
  • Cells, Cultured
  • Female
  • Gene Targeting*
  • Immunity, Innate
  • Inflammation / pathology
  • Lung / microbiology
  • Lung / pathology
  • Macrophages / cytology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nucleotide Motifs
  • Pseudomonas Infections / microbiology
  • Pseudomonas Infections / mortality
  • Pseudomonas Infections / pathology
  • Pseudomonas Infections / veterinary
  • Pseudomonas aeruginosa / genetics*
  • Pseudomonas aeruginosa / metabolism
  • Pseudomonas aeruginosa / pathogenicity
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Virulence / genetics

Substances

  • Bacterial Proteins
  • CRISPR-Associated Proteins
  • LasR protein, Pseudomonas aeruginosa
  • RNA, Messenger
  • Trans-Activators