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Study by UCSD gives new insight into how anthrax bacteria can evade a host's immune response

P> 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."


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Contact: Sherry Seethaler
sseethaler@ucsd.edu
858-534-4656
University of California - San Diego
6-Jan-2004


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