The body's overwhelming genetic defense, which has implications for the survival of patients who are severely burned or injured, was revealed in a sweeping analysis of gene activity in volunteers who were injected with a bacterial product that temporarily created flu-like symptoms.
"During a 24-hour period, the expression of more than 3,700 genes changed in blood leukocytes," said Lyle Moldawer, Ph.D., a surgery professor in the University of Florida College of Medicine, part of the national consortium that published the findings. "It was a dramatic reprioritization of genes. But beyond individual genes, we were able to look at networks, or functional modules of different gene clusters, that change in concordance with one another. We have now identified previously unknown relationships among different genes that tell us in greater detail how blood cells respond to an infectious challenge."
Inflammation is part of normal healing when people are severely burned or injured, but in some patients, it can be fatal, causing bloodstream infections and multiple organ failure. Learning how and why inflammation becomes harmful will help doctors more accurately predict how each injured patient will fare.
"This work represents a major step in understanding inflammation in severely injured or burned patients," said Jeremy M. Berg, Ph.D., director of the National Institute of General Medical Sciences, the component of the National Institutes of Health that funded the research. "We hope this knowledge eventually will help physicians better predict patient outcomes and tailor treatments accordingly."
UF Genetics Institute researchers are part of a national group of scientists united by a five-year, $37 million "glue grant" from the NIGMS. Glue grants bring together scientists from diverse fields -- in this case surgery, critical care medicine, genomics, bioinformatics, immunology and computational biology -- to solve problems in biomedical science that no single laboratory could address.
Scientists injected healthy volunteers with a microbial product that temporarily causes nausea and fever, triggering natural immune responses. The condition is similar to sepsis, which can happen when the body's infection-fighting white blood cells spring into action, causing potentially harmful inflammation in the process.
"Basically we made the volunteers appear septic for a couple of hours and examined changes in the gene expression from their white blood cells," Moldawer said. "Such genomic analyses give us the ability to simultaneously survey the activity of every gene in the cell, giving us vast lists of genes that change in response to stimulation. It provides us with an unprecedented amount of data."
To make sense of the enormous amount of information, researchers plugged their list of nearly 4,000 gene changes into a database of interactions of known human and mouse genes developed by Ingenuity Systems Inc. of Mountain View, Calif. The results identified the networks of genes that helped the body respond to the challenge.
"We were able to identify changes in functions that we never would have seen before," Moldawer said. "For example, the ability of the infection-fighting cells to make energy appeared to be down-regulated, as if the cells were shutting down all other functions not required to rid the body of the bacteria. This may well be the signal that something is wrong with the cell and may be a reason why some patients who are injured or infected go on to develop organ failure."
With that knowledge, scientists may be able to look at new ways to re-establish stability within the cells and avert the negative consequences of infection fighting.
"The apparent repression of genes that occurs has never been fully appreciated," said Henry Baker, Ph.D., associate director of the UF Genetics Institute and director of the UF lab that performs genomic analyses for the consortium. "Initially, more than half of the genes became less active, but over the long haul, they were more focused on the inflammatory response. By drawing samples for analysis over six time points in 24 hours, we were able to infer the sequence of events and how some changes in gene expression cause other changes."
Additional genomic analysis took place at the Stanford Genome Technology Center in Palo Alto, Calif., and the department of surgery at Washington University in St. Louis, Mo.
The research is particularly valuable because it plots inflammatory response over time, according to Scott D. Somers, Ph.D., NIGMS program director of this glue grant.
"In the case of injury, time is critical," Somers said. "To provide the best treatment, doctors need to know how the human body responds in the moments and days after an injury. No other study of injury or inflammation has tracked changes to the entire human genome over time."
The glue grant team includes scientists from the UF College of Medicine; Stanford; Washington University; the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School in New Brunswick, N.J.; Ingenuity Systems Inc.; the University of Rochester School of Medicine in Rochester, N.Y.; and Massachusetts General Hospital, Harvard Medical School in Boston.