Growth factor cocktail could reverse deadly effects of anthrax toxin

Anthrax, an infectious disease caused by the bacterium Bacillus anthracis, is often treatable in its early stages. But once the disease has progressed beyond the "point of no return" after just a few days, patients are almost certainly doomed.

In a new Nature Microbiology study, University of Pittsburgh researchers show that a cocktail of growth factors reversed would-be lethal cell damage in mice with anthrax, suggesting that this approach could be adapted for use in patients beyond the brink.

While only a few people die from anthrax in the United States each year, there is always the concern that the bacterium could be released on a large scale as a bioweapon. Because the early symptoms of anthrax are non-specific and flu-like, the disease often isn't diagnosed until it's too late for current treatments to help. We need new approaches to treat this later stage of the disease."

Shihui Liu, M.D., Ph.D., senior author, associate professor of medicine at the Pitt School of Medicine and member of the Aging Institute, joint venture of Pitt and UPMC

When B. anthracis enters the body through inhalation, ingestion, injection or contact with skin, it produces two proteins that combine to form lethal toxin.

Early on, anthrax can be treated with antibiotics that eliminate the bacterium or antibodies that neutralize lethal toxin before it enters cells. But once inside cells, the toxin inactivates members of a group of enzymes known as MEKs by cleaving off one of their ends, disrupting the important pathways they control and rapidly causing widespread cellular, tissue and organ damage-and death.

To learn more about the roles of MEK-controlled pathways in anthrax toxicity, Liu and his team generated mice with modified MEKs that were resistant to being cleaved by lethal toxin. These included MEK1 and MEK2, which control a pathway called ERK involved in cellular division and survival, and MEK3 and MEK6, which regulate the p38 pathway that's involved in stress-induced defense.

When exposed to lethal toxin or B. anthracis, mice with either modified MEK1/2 or MEK3/6 had much greater survival than normal animals, indicating that anthrax must inactivate both the ERK and p38 pathways to kill its host.

In mice and human cells exposed to lethal toxin or B. anthracis, a combination of three growth factors -all individually approved as treatments for other conditions – reactivated the ERK pathway and brought them back from the point of no return.

"Because lethal toxin breaks MEK proteins by clipping off their ends, we thought that this cellular damage was irreversible," said Liu. "So we were really surprised to find that specific growth factors were able to reactivate the ERK pathway and rescue the cell."

Because different types of cells in the body may require different growth factors to activate ERK, the researchers are now working to optimize a treatment for anthrax in humans.

Other authors on the study were Jie Liu, Ph.D., Zehua Zuo, Ph.D., Michael Ewing, Qing Cao, M.S., Qi Li, M.D., Ph.D., and Toren Finkel, M.D., Ph.D., all of Pitt and UPMC; Liu Cao, M.D., Ph.D., of China Medical University; and Stephen H. Leppla, Ph.D., of the National Institute of Allergy and Infectious Diseases (NIAID).

This research was supported by NIAID (R01AI170574).