New study may show how to forestall a fatal, virus-caused immune-system meltdown

February 14, 2007

GALVESTON, Texas -- When a virus infects a person, it triggers a series of biochemical reactions in immune-system cells that literally may have life or death consequences.

Usually, the result is an effective immune response, leading to the elimination of the virus and the infected person's recovery. But in the case of some of the world's deadliest pathogens -- including the Ebola, Marburg and Lassa fever viruses, as well as the influenza virus strain responsible for the 1918 flu pandemic -- the immune system itself actually becomes the most dangerous element of the disease. All too often, a sudden immune overreaction sends the infected person into a shock-like state from which he or she may never recover.

Now, researchers at the University of Texas Medical Branch at Galveston (UTMB) believe they've found a way to spot the biochemical profile of an inappropriate immune response to viral infection -- an important step toward developing new therapies that may head off or stop an otherwise fatal immune system meltdown.

In a paper published in the February 14 issue of the Journal of Virology, highlighted in the journal's "Spotlight" section and available now online, the scientists describe using a newly developed protein-scanning chip and a uniquely capable computer database to examine the activation and deactivation of more than a thousand proteins in cells from guinea pigs infected with two different strains of Pichinde virus. Guinea pigs infected with one of the Pichinde strains experience no ill effects, while those infected with the other strain develop symptoms similar to those seen in humans infected by the much more dangerous Lassa virus, which can cause an acute hemorrhagic fever and kills about 5,000 people a year in West Africa. (During some Lassa fever epidemics, as many as 50 percent of those diagnosed with the disease have died from it.)

"With these two forms of the virus and this new technology, we were able to compare pathogenic immune response and protective immune response on a broad, global level," said lead author and UTMB postdoctoral fellow Gavin Bowick. He said that checking almost 1,200 interactions simultaneously let the researchers see the big picture of immune response, avoiding the contradictory results often produced by studies that focus on only a single biochemical pathway.

To better understand their results, the investigators plugged their data into the Ingenuity Systems "pathways analysis" program, which draws on a large-scale computer database of biochemical interactions that have been described in a wide variety of peer-reviewed scientific papers. "Applying this massive Ingenuity database, which includes all sorts of cellular pathways that would normally not occur to us -- pathways discovered by people studying endocrinology, cancer, cystic fibrosis and so on -- we find that things suddenly begin to make sense," said UTMB professor Norbert Herzog, one of the paper's senior authors. "Cell signaling networks are like spider webs--pulling on one strand causes all the strands to move, and the Ingenuity system helped us see and comprehend connections we would have missed otherwise."

Connecting those strands is critical to diagnosing and restoring balance to an immune system gone haywire in a disease like Lassa fever. "Early on, you can't really differentiate these nasty hemorrhagic fever viruses from their symptoms -- they just resemble the flu," Herzog said. "But if you have biomarkers to go along with viral diagnostic techniques you can tell which virus it is and where you are on the continuum of infection. And if you understand the signaling pathways well enough, you can stimulate or suppress the immune response in the right way at the right time to create safe and effective therapies."

According to Bowick, the Pichinde experiments have already generated some therapeutic leads, thanks to the unexpected discovery that a growth factor receptor molecule normally associated with cancers was activated late in infection with the lethal strain of the virus. "We can go in and design an experiment where we can start testing drugs that already have FDA approval," Bowick said. "If we can go straight from discovery to drug candidates, that's quite a big leap for us, and one that may be very helpful, since there's really no incentive for drug companies to go out and develop new antiviral compounds for viruses that may or may not ever make it out of places like West Africa."

"This could be of critical importance to the people who live there, and for us if one of these diseases makes it across to here, either naturally like West Nile or as a result of bioterrorism," Bowick continued. He noted that the Lassa, Ebola and Marburg fever viruses have been identified as Category A biothreat agents by the National Institute of Allergy and Infectious Diseases (NIAID).

Other authors of the Journal of Virology paper included UTMB research associates Susan Fennewald, LiHong Zhang and Barry Elsom, associate professor of pathology Judith Aronson, biochemistry and molecular biology instructor Heidi Spratt, and biochemistry and molecular biology professors David Gorenstein and Bruce Luxon. Funding for the investigation was provided by the Defense Advanced Research Projects Agency, the National Institutes of Health, and the NIAID's Western Regional Center of Excellence for Biodefense and Emerging Infectious Disease Research.
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