Functional role of the type 1 pilus rod structure in mediating host-pathogen interactions.

Area of Science:

• Microbiology
• Structural Biology
• Infectious Diseases

Background:

• Uropathogenic E. coli (UPEC) are a major cause of urinary tract infections (UTI).
• Type 1 pili, a Chaperone Usher Pathway (CUP) pilus, are crucial virulence factors for UPEC, mediating gut colonization and UTI pathogenesis.
• The pilus rod, composed of FimA subunits, acts as a scaffold for the FimH adhesin and possesses unique mechanical properties.

Purpose of the Study:

• To determine the structure of the type 1 pilus rod and understand the molecular basis of its mechanical properties.
• To investigate the role of these mechanical properties in UPEC virulence and host-pathogen interactions.

Main Methods:

• Cryo-electron microscopy was used to solve the 4.2 Å resolution structure of the type 1 pilus rod.
• Sequence analysis of fimA genes identified conserved residues critical for mechanical properties.
• Mutant pili with altered mechanical properties were generated and tested in vitro and in vivo.

Main Results:

• The study determined the high-resolution structure of the type 1 pilus rod, revealing key residues governing its mechanical resilience.
• Mutations were identified that reduced the force required to unwind the pilus rod without affecting in vitro production.
• UPEC strains expressing these weakened pili exhibited significantly reduced virulence in mouse models of bladder infection and intestinal colonization.

Conclusions:

• The mechanical spring-like property of type 1 pilus rods is essential for UPEC virulence.
• Targeting these mechanical properties offers a potential new strategy for combating UPEC infections.
• This finding has broader implications for understanding and treating other diseases mediated by similar pilus structures.