Study reveals E. coli's secret weapon in launching infections
Most types of Escherichia coli are harmless, but those that are not can cause severe life-threatening diarrhea. These problematic bacteria trigger infections by inducing intestinal cells to form tiny structures, called pedestals, that anchor the pathogens in place and help colonies grow.
This week in mBio, microbiologists describe an Achilles heel to disable pedestal formation. Laboratory experiments on enteropathogenic and enterohaemorrhagic E. coli (EPEC and EHEC) showed that when pathogens were prevented from injecting a protein called EspG into intestinal hosts, hosts were slower and less effective at producing pedestals that bound bacteria in place. Other investigations have revealed the cellular pathways diverted by EspG.
The results can help reveal the mechanisms of infection and suggest new avenues for treatment, said microbiologist and co-director of the study, Peter Hume, PhD, at the University of Cambridge, UK.
"By learning how these pathways work, we believe we can develop new ways to interfere with the infection process," he said.
Worldwide, more than 500,000 children die each year from diarrhoeal diseases and pathogenic strains of E. coli are among the most common causes, according to the World Health Organization. But treating these infections can be tricky. The use of antibiotics to treat a person with EHEC, for example, can trigger the release of Shiga toxin from the bacteria, which can lead to a life-threatening infection similar to sepsis. This means that health care providers need treatments other than antimicrobials to control these infections, Hume said.
Researchers have long known that pathogenic E. coli injects its host with a variety of proteins, including EspG. So far, however, these interactions have only been linked to other biochemical functions. "People had already tried to find a link to the pedestals, but they never found one," says Hume, whose work focuses on how bacterial pathogens affect the cytoskeletons of host cells. This study was conducted in the laboratory of Vassilis Koronakis by Hume in collaboration with his Cambridge colleagues Vikash Singh and Anthony Davidson.
Previously, researchers studied the effects of EspG on macrophages, and these results suggest that the protein may have a neglected role in pedestal formation in intestinal hosts.
For this study, they infected a group of Hap1 cells with wild-type EHEC and EPEC, and another with the same types of E. Coli, but without the genes responsible for the production of EspG. Using fluorescence microscopy, the researchers studied the results. E. coli infected cells without EspG took longer to produce pedestals than those of wild strains, and the pedestals that were produced were shorter.
Follow-up experiments have shown that the EspG protein diverts the host cell by trapping an active enzyme called PAK. Although previous work has shown a link between EspG and PAK, the new study is the first to link both to pedestal formation.
This link could also help researchers studying other diseases. 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 an impact on other pathogens that manipulate the same pathways of penetration," said Hume.
