Genes in pathogenic E. coli may suppress, not exacerbate, inflammation

May 19, 2007

Some patients may be especially susceptible to urinary tract infections, and some uropathogens may be particularly virulent. But that's not the whole story. Virulent bacteria, in fact, may actually change their hosts' immune systems to break through their defenses.

Some patients may be especially susceptible to urinary tract infections, and some uropathogens may be particularly virulent. But that's not the whole story. Virulent bacteria, in fact, may actually change their hosts' immune systems to break through their defenses.

Now a team from Northwestern University's Feinberg School of Medicine in Chicago has uncovered the genes in pathogenic Escherichia coli likely responsible for suppressing the host defenses. And those genes do something clinicians don't expect-they suppress inflammation instead of exacerbating it. That may mean urologists need to think differently about helping patients early on in the course of a UTI, and it may also mean that that vaccines might be in the offing.

Virulent E. coli have the capability to suppress inflammatory pathways, particularly the NF kappa B pathway. They also potentiate apoptosis, extending their opportunity to establish intracellular reservoirs, explained David Klumpp, PhD, who presented the findings here yesterday.

Now the team knows more about how the bacteria disrupt these pathways. They created a library of mutant bacteria, inoculated urothelial cells, and looked for changes in cytokine secretion. The mutant strains that suppressed IL-8 secretion mapped to three different genes, all associated with a loss of NF kappa B suppressive activity. The investigators then confirmed that gene deletions did indeed recap the mutant strains they created, so they're likely on target with the genes for this virulence.

Another surprise was that these genes don't seem to help bacteria convey a factor to the host's cytosol. Instead, the genes map to the bacterial cell wall.

"In the future," said Dr. Klumpp, "we need to figure out how changes in cell wall structure are inhibiting these pathways, but the component of virulence seems to be changing the host response to otherwise inflammatory cell surface determinants."

"This is contrary to what one might have expected," commented moderator John Krieger, MD, of the University of Washington, Seattle. "Urologists might not want to reduce inflammation. They might want to give a pro-inflammatory drug."

In addition, said Dr. Klumpp, "Urovirulence of these bacteria is attenuated, which means that a strain like this could perhaps someday be used as an attenuated live vaccine, because you would imagine that it would stimulate a similar type of immune response as the wild type E. coli but it doesn't have virulence and it's not going to persist in its host."