Crucial Pathway Discovered to Fight Gut Infection / Inflammatory Bowel Diseases

Researchers discover crucial pathway to fight gut infection

http://newsroom.melbourne.edu/news/researchers-discover-crucial-pathway-fight-gut-infection

The researchers found virulent E. coli bacteria blocked a pathway that would normally protect the gut from infection. These infections are particularly serious in young children and can result in diarrhoea and other complications such as kidney damage.

The role of this pathway in fighting gut infection was previously unknown but defects in it are associated with inflammatory bowel disease.

The research, published tomorrow in Nature, provides much needed insight into how the gut fights infection.

Lead author Professor Elizabeth Hartland from the University’s Department of Microbiology and Immunology said the research improved our understanding of what happens when this pathway doesn’t work as well as it should.

“This research provides a model where we can look at how these bacteria switch off a critical pathway in our body that helps fight infection and contributes to normal intestinal function,” she said.

“Using this fundamental knowledge, we can conduct further studies and work towards improving therapies and treatments for people with inflammatory bowel disease, which affects around 5 million people worldwide”

The researchers found the diarrhoea-causing bacteria use a needle-like structure to inject a toxin into the gut cell that blocks cell death. This allows the bacteria to survive and spread in the gut, causing a range of diseases. 



The injected toxin paralyses the infected cell’s ability to send messages to immune cells which would normally sense and eliminate dangerous microbes from the body as well as alert the broader immune system to mount a response to the infection.

“This is a significant contribution to global research in this field as the role of this pathway in intestinal defence and the way bacteria go about blocking this pathway was not known.”

Diarrhoeal infections are predominantly a problem in developing countries where sanitation is poor, yet cases of virulent E. coli also occur in developed countries including Australia.

The international study was conducted in collaboration with the Walter and Eliza Hall Institute, Bio21 Institute and international universities.

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A type III effector antagonizes death receptor signalling during bacterial gut infection

http://www.nature.com/nature/journal/v501/n7466/full/nature12524.html

Successful infection by enteric bacterial pathogens depends on the ability of the bacteria to colonize the gut, replicate in host tissues and disseminate to other hosts.

Pathogens such as Salmonella, Shigella and enteropathogenic and enterohaemorrhagic (EPEC and EHEC, respectively) Escherichia coli use a type III secretion system (T3SS) to deliver virulence effector proteins into host cells during infection that promote colonization and interfere with antimicrobial host responses1, 2, 3.

Here we report that the T3SS effector NleB1 from EPEC binds to host cell death-domain-containing proteins and thereby inhibits death receptor signalling.

Protein interaction studies identified FADD, TRADD and RIPK1 as binding partners of NleB1. NleB1 expressed ectopically or injected by the bacterial T3SS prevented Fas ligand or TNF-induced formation of the canonical death-inducing signalling complex (DISC) and proteolytic activation of caspase-8, an essential step in death-receptor-induced apoptosis.

This inhibition depended on the N-acetylglucosamine transferase activity of NleB1, which specifically modified Arg 117 in the death domain of FADD. The importance of the death receptor apoptotic pathway to host defence was demonstrated using mice deficient in the FAS signalling pathway, which showed delayed clearance of the EPEC-like mouse pathogen Citrobacter rodentium and reversion to virulence of an nleB mutant. The activity of NleB suggests that EPEC and other attaching and effacing pathogens antagonize death-receptor-induced apoptosis of infected cells, thereby blocking a major antimicrobial host response.

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