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Flagellar switch inverted repeats impact heterogeneity in flagellar gene expression and thus C. difficile RT027/MLST1

Nguyen T Q Nhu1, Huaiying Lin2, Ying Pigli3

  • 1Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Duchossois Family Institute, University of Chicago, Chicago, IL 60637, USA.

Cell Reports
|June 12, 2025
PubMed

Insights

Clostridioides difficile RT027 strains show variable infection severity. Greater flagellar gene expression heterogeneity in these C. difficile strains correlates with increased virulence and disease severity.

Area of Science:

  • Microbiology
  • Infectious Diseases
  • Genetics

Background:

  • Clostridioides difficile (C. difficile) RT027 strains cause a spectrum of infections, from mild to life-threatening.
  • The molecular mechanisms underlying this variability in C. difficile infection severity remain unclear.

Purpose of the Study:

  • To investigate the relationship between flagellar gene expression heterogeneity and virulence in C. difficile RT027 clinical isolates.
  • To elucidate the genetic basis for variable flagellar gene expression in C. difficile.

Main Methods:

  • Comparative analysis of C. difficile RT027 clinical isolates.
  • Examination of flagellar gene expression patterns.
  • Correlation analysis between inverted repeat (IR) sequence length, gene expression heterogeneity, and in vivo virulence.

Main Results:

  • Isolates with greater flagellar gene expression heterogeneity demonstrated higher virulence in vivo.
  • Phase-variable expression of C. difficile flagellar genes is controlled by site-specific inversion of the flgB 5' UTR.
  • Longer IR sequences in the switch region, specifically 6A/6T IRs, were associated with greater phenotypic heterogeneity (60%-75% ON) and more severe disease outcomes compared to shorter IRs (>99% ON or OFF).

Conclusions:

  • Phenotypic heterogeneity in flagellar gene expression is a potential contributor to the variable severity of C. difficile infections.
  • The length of IR sequences in the flagellar switch region influences gene expression heterogeneity and C. difficile virulence.
Keywords:
CP: MicrobiologyClostridioides difficileRT027flagellar switchinverted repeatsrecombinasevirulence

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