Biologists at the University of California, San Diego have determined how toxin produced by anthrax bacteria blocks a person's normal immune response, a discovery that could lead to new treatments for anthrax infection.
In a paper to be published in the January 15th issue of The Journal of Immunology the UCSD scientists show why, in the presence of anthrax toxin, human immune cells fail to respond normally to lipopolysaccharide--a component of the cell walls of many bacteria including the bacteria that cause anthrax, Bacillus anthracis. Bacterial invasion, or the presence of lipopolysaccharide, usually causes immune cells known as macrophages to release cytokines--chemicals that signal other cells about the presence of an invader. Release of cytokines causes large numbers of immune cells to arrive at the site of infection and destroy the bacteria. By blocking this host immune response, anthrax bacteria are able to multiply unchecked. According to the Centers for Disease Control, approximately 75 percent of people infected with inhalation anthrax die, even with all possible supportive care including appropriate antibiotics.
"Although it was known for quite some time that anthrax toxins can suppress cytokine production, the mechanism by which Bacillus anthracis escapes the immune response isn't really understood," says Michael David, a biology professor at UCSD who headed the research team. "We have identified a protein molecule targeted by the anthrax toxin and determined where it acts in the sequence of steps involved in immune response."
Macrophages have special receptors on their surfaces that bind to lipopolysaccharide. The binding of lipopolysaccharide to this receptor sets off a sequence of events inside the macrophage, in which a series of proteins activate one another in turn. This cascade of proteins activating one another ultimately turns on cytokine genes, causing the macrophage to churn out large quantities of cytokines.
It turns out that there are two separate, sometimes cooperating, routes in the cell by which series of proteins activate one another to switch on production of cytokines. One of the routes has been recognized for a long time, but researchers were sometimes puzzled when cytokine production was turned on or off without the proteins along this route being activated or deactivated. This puzzle was resolved when the David group and other groups simultaneously identified the second route, the IRF3 pathway. The anthrax toxin targets the IRF3 pathway by cleaving MKK6--one of the proteins in the series along the route. The cleavage of MKK6 prevents the cytokine genes from being switched on.
When the researchers made mutant macrophages with a variant of MKK6 that could not be cleaved by the anthrax toxin, these macrophages responded to lipopolysaccharide by producing cytokines even in the presence of the anthrax toxin. This suggests that developing a drug that could protect MKK6 and prevent anthrax toxin from cleaving it could help to prevent an anthrax infection from getting out of control. The anthrax bacteria would be unable to evade the normal immune response.
"While these results may not lead to a drug to cure anthrax in the next six months, the more you understand about bacteria and how they target the immune response the more options you have for developing drugs to treat the infections," says David.
Previous work by other researchers has suggested that anthrax toxin evades the immune system by killing macrophages; however, according to David, cell death does not fully explain how anthrax bacteria evade the immune system.
"Only some types of macrophages are killed by anthrax toxins, but anthrax toxins diminish the production of cytokines in all of the macrophages we have tested," David explains. "Also, less toxin is needed to shut off the immune response than to kill the macrophages."
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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