New clue hints at how anthrax kills.

Nicholas S. Duesbery never expected to find a clue to the deadliness of a microorganism feared by biological warfare experts. His studies focus on a signaling pathway inside cells that depends upon a protein called mitogen-activated protein kinase (MAPK). This pathway is employed by many kinds of cells, including cancer cells and immature mammalian eggs, or oocytes.

"I wanted to find something that inhibits the MAPK pathway so that I could see what happens to cancer cells and oocytes," says Duesbery, who works at the National Cancer Institute (NCI) in Frederick, Md.

Searching through an NCI database that stores information on how thousands of compounds affect 60 kinds of cancer cells, Duesbery and his colleagues found one whose actions closely resembled those of a previously identified inhibitor of the MAPK pathway. Much to their surprise, this compound turned out to be a key component of the deadly toxin made by the bacterium Bacillus anthracis.

Though microscopic, B. anthracis could prove a devastating weapon in the hands of armies or terrorists. Its toxin, commonly known as anthrax, acts swiftly. A small dose can kill a rat in less than hour, apparently by destroying immune cells called macrophages.

Yet investigators have not had many clues as to how the toxin kills cells. It consists of three proteins, the most deadly of which is named lethal factor (LF). It was LF that Duesbery came upon in his quest for a MAPK pathway inhibitor.

Duesbery and his colleagues next obtained a sample of LF and tested whether it disrupts the MAPK pathway in oocytes. "It blocked the oocytes' ability to develop into eggs," says Duesbery. In further experiments, described in the May 1 Science, the scientists discovered that LF inhibits the MAPK signaling pathway by cleaving other proteins that would normally activate MAPK.

The scientists are still working to confirm that LF's inhibition of the MAPK pathway explains the deadliness of anthrax. They're investigating how macrophages react to disruptions of this signaling system by other methods, for example. If MAPK inhibition is the explanation for anthrax's actions, says Duesbery, compounds that block LF's cleaving action--so-called protease inhibitors--might be a useful therapy for the disease.