Health News
Scientists get look at genes' defensive playbook
August 2005
GAINESVILLE, Fla. - Using a new method to identify networks of infection-fighting genes, scientists writing in today's (8-31) online edition of Nature say more than 15 percent of our genes are mobilized to defend against microbial attacks.
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.
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Anthrax stops body from fighting back,
study shows
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August 2005
GAINESVILLE, Fla. - University of Florida researchers have uncovered how the inhaled form of anthrax disarms bacteria-fighting white blood cells before they can fend off the disease, which kills most victims within days.
The lethal toxin in anthrax paralyzes neutrophils, the white blood cells that act as the body's first defense against infection, by impairing how they build tiny filaments that allow them to crawl throughout the body and eat invading bacteria.
Just two hours of exposure to the lethal toxin blocks the neutrophils' ability to produce these filaments by nearly 60 percent, paralyzing them and allowing the anthrax to move freely in the body, according to research released last week in The Journal of Infectious Diseases.
The need to find new ways to treat victims of bioterrorism has increased since the Sept. 11, 2001, terrorist attacks and the anthrax attacks that killed five people exposed to inhalation anthrax through the mail. The UF findings could lead to treatments that block anthrax from paralyzing the much-needed neutrophils, said Frederick Southwick, M.D., division chief of infectious diseases at the UF College of Medicine and the lead author of the paper.
"If your neutrophils work normally, you might be able to shut down this infection," said Southwick, who worked on the study with a team of UF researchers and investigators from the Centers for Disease Control and Prevention and Emory University. "The overall goal is to understand how anthrax toxins paralyze the immune system."
Researchers first noticed anthrax's effect on these white blood cells while reviewing the cases in the 2001 anthrax attacks. The victims did not have elevated white blood cell counts, typical for most infections, and a large number of the inhaled anthrax bacteria had spread from the lungs into the bloodstream, which is unusual, Southwick said.
This led researchers to believe anthrax may be impairing the cells' ability to move and fight off the offending bacteria, an idea that had only been studied once before years earlier.
Using blood samples from volunteers, the researchers studied how neutrophils reacted when exposed to a purified form of anthrax lethal toxin, the part of the spore linked to the illness. Unlike an intact inhalation anthrax spore, the pure toxin is not dangerous for researchers to use and allows them to isolate specifically how the toxin is affecting cells, Southwick said.
Low doses of the lethal toxin stopped the protein actin from building filaments to steer the neutrophils, stopping the body's immune response, the study found.
"Neutrophils crawl around in the body and roll around in the blood vessels and whenever they sense bacteria, they gobble it up like Pac-Man," said Russell During, a graduate student in the Interdisciplinary Program in Biomedical Sciences who worked with Southwick on the study. "If neutrophils are the first responders and they never get there, you're fighting a losing battle."
And inhalation anthrax works fast, which is one of the reasons why it is usually fatal, according to the CDC. The disease can be treated with antibiotics, but people often don't seek treatment until it is too late, said Philip C. Hanna, Ph.D, an associate professor of microbiology and immunology at the University of Michigan Medical School.
"A person can die before they know they are terribly sick at all," Hanna said.
Symptoms of inhalation anthrax resemble the common cold and progress to breathing problems, shock and often death, according to the CDC.
But in the 2001 attacks, only half the 10 people who contracted inhalation anthrax died. The five other victims were diagnosed and treated earlier due to quick communication from the doctors who pinpointed the first anthrax infection, Southwick said. Twelve other people contracted cutaneous (skin) anthrax infections, which are not usually fatal.
Knowledge about anthrax and how it works has improved since then, too, Hanna said. Now doctors know what anthrax looks like and what public health steps to take, he added.
The next step for UF researchers is to pinpoint the exact protein the lethal toxin is targeting in the neutrophil. There are more than 100 proteins that regulate actin-filament formation, and researchers have already isolated one that may be responsible, Southwick said.
The UF findings also could affect research on other diseases. Because actin is found in every cell, the study could lead researchers to know more about how tumors and other cells move in the body, Southwick said.
"It relates to wound healing, it may relate to many diseases and many problems," he said.
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