E. coli has earned its reputation as a deadly pathogen lurking in contaminated foods, but a multi-year study may give it some positive press as a source of medical knowledge and potential therapeutics.
Researchers at Kansas State University are studying a protein secreted by E. coli bacteria that blocks functions of the body's innate immune system with the hope of uncovering information that could improve understanding of how E. coli infects humans – and possibly help find therapies for a number of other diseases in the process.
Successful study of the protein could also translate into the development of better E. coli surveillance tools, or possibly provide insight into how to treat E. coli infections, said research lead Dr. Philip Hardwidge, associate professor at KSU's College of Veterinary Medicine. The project is being funded through a multi-year grant from the National Institutes of Health.
The protein in question (known as "NleH1″) is encoded by pathogenic E. coli strains that reside within cattle and subsequently infect humans. It inhibits a cellular signaling pathway in mammals called IKK/N-F-Kappa-B, an important regulator of the immune system that provides a first line of defense against infection.
In short, the E. coli bacterium injects the protein directly into the infected host's intestinal cells and effectively prevents the body's immune system from defending against infection by silencing its ability to signal the immune system.
While the ultimate goal of the research is to provide a better biochemical understanding of the protein, the team's potential insights could also benefit a range of other research.
First, the research may reveal molecular strategies of how E. coli targets host cells, leading to potential therapies against E. coli infection. Because the protein is injected directly from the bacterium into the host's cells, it's difficult to target the protein directly, but other drug therapies may become possible with a better understanding of how the protein disrupts the immune system, Hardwidge said.
The protein may also provide new tools for detecting potentially harmful strains of E. coli. Since NleH1 tends to be expressed primarily in virulent E. coli strains and not as frequently in strains harmless to humans, there may be ways to screen E. coli to detect new, potentially harmful strains before they cause an outbreak.
"In terms of being able to recognize and respond to potential future threats, it becomes important to not just wait for an outbreak to occur and then say, 'Oh, this is dangerous,'" Hardwidge said.
Instead, he explained, it could be possible to use technologies to infer which strains might have the potential to cause a future outbreak. As new virulent strains are likely to evolve over time, cattle populations could theoretically be screened to see if any new strains possess NleH1 or a group of other proteins that also inhibit the host immune system, thus tipping researchers off to a potential threat.
A better grasp of the protein's molecular mechanism of action could also lead to a range of anti-inflammatory therapeutics. Because the protein suppresses the body's immune modulators that trigger inflammation, it could theoretically provide a novel way to treat inflammatory diseases unrelated to E. coli infections, such as Crohn's disease, colon cancer, and inflammatory bowel disease.
The strategy would be similar to many other immunosuppressive therapies already working to treat patients with inflammatory diseases, but it would rely on a protein already evolved in an organism instead of by screening small molecules selected from chemical libraries using trial and error.
"Bacteria and viruses have already evolved very effective ways of inhibiting the inflammatory components of the immune system," Hardwidge said. "Why not utilize this existing information, use that as a starting point, and refine those proteins into potential therapeutics?"
The idea of deriving such therapies is still emerging, but has the potential to add a new class of compounds to the armament of treatment strategies used against inflammatory diseases, he noted.
"This research will provide very basic information about how bacterial pathogens are able to disrupt or inhibit the innate immune system of the infected intestinal cell," Hardwidge said. "Having a basic understanding at a very detailed molecular level has also revealed a lot about the normal functioning of the innate immune system."
