Most types of Escherichia coli are harmless, but the ones that aren’t can cause life-threatening diarrhea. These problematic bacteria launch infections by inducing intestinal cells to form tiny structures called pedestals that anchor the pathogens in place and help the colonies grow. In a study published today in mBio, scientists were able to diminish pedestal formation.
Lab experiments on enteropathogenic and enterohemorrhagic E. coli (EPEC and EHEC) showed that when the pathogens were prevented from injecting a protein called EspG into intestinal hosts, the hosts were slower and less effective in producing pedestals that fixed the bacteria in place. Further investigations revealed the cellular pathways that were hijacked by EspG.
“By learning how these pathways work, we think we can develop new ways of interfering with the infection process,” says coauthor Peter Hume of the University of Cambridge.
Worldwide, more than 500,000 children die every year from diarrheal diseases, and pathogenic strains of E. coli are among the most common causes, according to the World Health Organizations. But treating these infections can be tricky. Using antibiotics to treat a person with EHEC, for example, can trigger the bacteria to release Shiga toxin, which can lead to a life-threatening infection similar to sepsis. That means health care providers need treatments other than antimicrobials to keep these infections in check, Hume says.
Researchers have long known that pathogenic E. coli injects its host with a variety of proteins, including EspG. Until now, however, those interactions have been linked only to other biochemical functions.
For the current study, the team infected one group of Hap1 cells with wild-type EHEC and EPEC, and they infected another with mutated EHEC and EPEC that lacked the genes responsible for producing EspG. Using fluorescence microscopy, the researchers found that cells infected by E. coli lacking EspG took longer to produce pedestals than the others, and the pedestals they did produce were shorter.
Follow-up experiments revealed that the EspG protein hijacks the host cell by scavenging an active enzyme called PAK. Although previous work has shown a link between EspG and PAK, the new study is the first to connect the two to the formation of pedestals.
That connection may help researchers studying other diseases, as well. PAK has been implicated in some cancers, and other studies have shown that some viruses—including HIV—can activate it.
“This study may well have implications with other pathogens that manipulate the same pathways,” Hume says.