Infection-induced membrane ruffling initiates danger and immune signaling via the mechanosensor PIEZO1

Area of Science:

• Cell Biology
• Immunology
• Biophysics

Background:

• Microbial recognition typically involves receptors detecting molecular patterns.
• Bacterial pathogens trigger intestinal epithelial cells to release ATP, a danger signal, initiating inflammation.
• The precise trigger for ATP secretion during bacterial infection remains unknown.

Purpose of the Study:

• To investigate the mechanism by which bacterial entry triggers ATP secretion in intestinal epithelial cells.
• To determine if physical forces, rather than molecular cues, play a role in initiating immune signaling during infection.

Main Methods:

• Utilized PIEZO1, a known mechanosensitive channel, as a potential sensor for bacterial invasion.
• Applied mechanical stimuli mimicking pathogen entry using sterile beads.
• Employed chemical and genetic methods to inactivate or activate PIEZO1.
• Measured calcium (Ca2+) influx and ATP secretion.
• Analyzed gene expression related to immune and barrier pathways.

Main Results:

• PIEZO1 mechanically senses bacterial entry via invasion-induced membrane ruffles, preceding Ca2+ influx and ATP secretion.
• Mechanical stimulation with beads replicated ATP secretion, confirming the role of physical forces.
• PIEZO1 inactivation blocked mechanically induced ATP secretion.
• PIEZO1 activation led to gene expression changes in immune and barrier pathways.

Conclusions:

• Mechanosensation of plasma membrane distortion during bacterial invasion is a key initiator of immune signaling.
• PIEZO1 acts as a physical sensor for infection, independent of detecting microbial molecules.
• Infection detection relies on physical cues, highlighting a novel mechanosensory pathway in immunity.