Cheating by type 3 secretion system-negative Pseudomonas aeruginosa during pulmonary infection

Proc Natl Acad Sci U S A. 2014 May 27;111(21):7801-6. doi: 10.1073/pnas.1400782111. Epub 2014 May 12.

Abstract

The opportunistic pathogen Pseudomonas aeruginosa expresses a type 3 secretion system (T3SS) strongly associated with bacterial virulence in murine models and human patients. T3SS effectors target host innate immune mechanisms, and T3SS-defective mutants are cleared more efficiently than T3SS-positive bacteria by an immunocompetent host. Nonetheless, T3SS-negative isolates are recovered from many patients with documented P. aeruginosa infections, leading us to test whether T3SS-negative strains could have a selective advantage during in vivo infection. Mice were infected with mixtures of T3SS-positive WT P. aeruginosa plus isogenic T3SS-OFF or constitutively T3SS-ON mutants. Relative fitness of bacteria in this acute pneumonia model was reflected by the competitive index of mutants relative to WT. T3SS-OFF strains outcompeted WT PA103 in vivo, whereas a T3SS-ON mutant showed decreased fitness compared with WT. In vitro growth rates of WT and T3SS-OFF bacteria were determined under T3SS-inducing conditions and did not differ significantly. Increased fitness of T3SS-OFF bacteria was no longer observed at high ratios of T3SS-OFF to WT, a feature characteristic of bacterial cheaters. Cheating by T3SS-OFF bacteria occurred only when T3SS-positive bacteria expressed the phospholipase A2 effector Exotoxin U (ExoU). T3SS-OFF bacteria showed no fitness advantage in competition experiments carried out in immunodeficient MyD88-knockout mice or in neutrophil-depleted animals. Our findings indicate that T3SS-negative isolates benefit from the public good provided by ExoU-mediated killing of recruited innate immune cells. Whether this transient increase in fitness observed for T3SS-negative strains in mice contributes to the observed persistence of T3SS-negative isolates in humans is of ongoing interest.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Bacterial Secretion Systems / immunology*
  • Coinfection / immunology*
  • Cytokines / immunology
  • DNA Primers / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Exotoxins / metabolism
  • Flow Cytometry
  • Mice
  • Microscopy, Fluorescence
  • Plasmids / genetics
  • Pneumonia / immunology*
  • Pneumonia / microbiology
  • Pseudomonas Infections / immunology*
  • Pseudomonas aeruginosa / growth & development
  • Pseudomonas aeruginosa / immunology*

Substances

  • Bacterial Secretion Systems
  • Cytokines
  • DNA Primers
  • Exotoxins