Cracking the Virulence Code
U-M research makes strides in fight against major worldwide killer
While Escherichia coli bacteria are part of the normal flora of the human digestive system, harmful strains of E. coli kill 1 million people worldwide each year and sicken 160 million more. Children in the developing world are hit hardest, though Western, industrialized countries also experience outbreaks — a particularly virulent strain traced to bean sprouts killed dozens of people in Germany last year.
“Most bacterial infections are controlled by antibiotics, but with severe E. coli infections the patients actually do worse. Typically you take them to the hospital, put them on IV fluids and just pray for the best,” says Gabriel Núñez, M.D., the Paul H. de Kruif Professor of Pathology in the Medical School.
Núñez and postdoctoral fellow Nobuhiko Kamada, Ph.D., are helping to unravel fundamental questions about how infectious E. coli interacts with non-pathogenic E. coli and other microbes inside the gut — which, in turn, may lay the groundwork for new clinical approaches.
“On one side you have basic questions about how the microbiota in the gut and the pathogen try to control each other, but we’re also gaining insights into fighting these infections,” says Núñez. Research led by the U-M duo was recently published in Science magazine.
The scientists compared the response of conventionally raised mice and germ-free mice — which do not have normal, “good” bacteria living in their digestive systems — to Citrobacter rodentium, which serves as a model for human infections of enterohemorrhagic and enteropathogenic E. coli.
For both types of mice, the C. rodentium load rises dramatically over the first seven days. In those with normal flora, known as commensals, the infections drop until they are eliminated by day 21, while the germ-free mice maintain a steady, high load — indicating healthy gut bacteria are necessary for the eradication of the pathogen. But something left the scientists scratching their heads.
“We expected the germ-free mice to be overwhelmed by the infections,” Núñez says. “That all the mice survived was very shocking to us, but it was good because it showed us that there was something important that we didn’t understand.”
The key lay in an island of genes whose expression regulates the bacteria’s virulence. Early expression of virulence genes helps the pathogen out-compete the existing microbiota and establish itself on the intestinal lining. Then, after about a week, virulence expression is down-regulated and the bacteria move to the open center of the intestine, where they are eventually competed into extinction — but not before the diarrhea they cause provides an escape route for some of them, allowing them to leave the body and seek new hosts.
“From the point of view of evolution, the pathogen and host shake hands in a very important agreement. The pathogen is allowed to multiply, but eventually virulence gets turned off, which allows both to survive,” Núñez says.
The researchers found that changing the balance of dietary sugars can help tip the scales against the invaders. They also discovered that when a factor activating the expression of virulence genes was missing, commensals could out-compete and decimate the invading pathogen in the early days of an infection — suggesting it may be possible to greatly lessen the effects in humans by tricking virulence genes into turning off early.
“We are very optimistic. The drugs would simply need to mimic what nature does,” Núñez adds, noting that his lab is continuing to study the mechanisms underlying virulence regulation, and collaborating with others at the U-M to identify potential therapeutic agents. —IAN DEMSKY