Immune protein helps cells detect bacterial attacks on the cytoskeleton

Study reveals a new defence mechanism against diarrhoea-causing bacteria

Researchers have identified a new way that human cells detect infection by extracellular Gram-negative bacteria, revealing how the immune protein GBP1 responds to bacterial manipulation of the host cell’s actin cytoskeleton.

The study, published in The EMBO Journal, was led by researchers at Imperial College London and collaborators at the Francis Crick Institute, the University of Geneva and other institutions. Dr Wouter Kallemeijn from the Tate Research Group contributed to this study.

The team investigated enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC), which attach tightly to intestinal cells and hijack the actin cytoskeleton to build distinctive ‘pedestals’ beneath the bacteria. Using human cell models, intestinal organoids and a mouse model of infection, the researchers found that GBP1 is recruited to these actin-rich structures, where it helps bring the inflammatory enzyme caspase-4 to the site of bacterial attachment.

This recruitment initiates a form of inflammatory cell death known as pyroptosis, together with the release of the immune signalling molecule IL-18. The response depended on bacterial effector-driven actin polymerisation and was observed both in cultured human cells and in mouse colon tissue infected with the EPEC-like pathogen Citrobacter rodentium.

Importantly, the researchers showed that GBP1 is attracted to the sites of actin remodelling independently of lipopolysaccharide (LPS), a bacterial molecule that GBP1 is already known to recognise. A synthetic system that recreated actin polymerisation without bacteria or LPS also recruited GBP1 and caspase-4, demonstrating that manipulation of the cytoskeleton itself can act as an alarm signal.

The findings expand the known role of GBP1 from recognising bacterial components to detecting the effects of bacterial virulence factors. This provides a new example of ‘effector-triggered immunity’, in which host cells respond to the activity of pathogen proteins rather than only to the presence of the pathogen.

The research team suggest that this mechanism may help intestinal cells remove niches created by attaching-and-effacing bacteria, including pathogens associated with severe diarrhoeal disease. Further work will be needed to determine whether GBP1 responds to other pathogens that manipulate the actin cytoskeleton and how this pathway could be influenced in disease.