A new study, published in The EMBO Journal and led by researchers at Imperial College London in collaboration with institutions including the Francis Crick Institute and the University of Geneva, has uncovered how human cells detect infections by extracellular Gram-negative bacteria. The research focuses on the immune protein GBP1 and its role in responding to bacterial manipulation of the cell's actin cytoskeleton.
The team investigated enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC), bacteria known to attach to intestinal cells and hijack the actin cytoskeleton to form 'pedestals'. Using human cell models, intestinal organoids, and a mouse model, they found that GBP1 is recruited to these actin-rich structures. This recruitment facilitates the arrival of the inflammatory enzyme caspase-4 to the site of bacterial attachment.
This process triggers inflammatory cell death, known as pyroptosis, and the release of the immune signalling molecule IL-18. The response was observed in cultured human cells and in mouse colon tissue infected with Citrobacter rodentium, a pathogen similar to EPEC. Crucially, GBP1 was attracted to actin remodelling sites independently of lipopolysaccharide (LPS), a bacterial molecule it is already known to recognise. A synthetic system recreating actin polymerisation without bacteria or LPS also recruited GBP1 and caspase-4, indicating that cytoskeleton manipulation itself serves as an alarm signal.
These findings expand the known function of GBP1 beyond recognising bacterial components to detecting the effects of bacterial virulence factors. This exemplifies 'effector-triggered immunity', where host cells react to the activity of pathogen proteins. The research suggests this mechanism may help intestinal cells eliminate niches created by attaching-and-effacing bacteria, including those causing severe diarrhoeal diseases. Further research is planned to explore GBP1's response to other pathogens that manipulate the actin cytoskeleton and its potential influence in disease.
