EMBARGOED BY SCIENCE FOR 2 p.m. EDT THURSDAY, AUG. 29, 2002
Molecular Mechanism Underlying Anthrax Infection
Described By UCSD School Of Medicine Researchers
The mechanism by which inhaled anthrax disarms and evades the immune system, enabling the potentially lethal bacteria to rapidly spread throughout the body, has been described by researchers at the University of California, San Diego (UCSD) School of Medicine.
Published online Aug. 29 in Science Express, the website of the journal Science, the lab-culture research with mouse cells describe how a complex of Bacillus anthracis (anthrax) proteins called lethal toxin (LT) inhibits and destroys macrophages, the large white blood cells that act as the body's first defense against pathogens, and also disables the signaling mechanism triggering immune activation. This allows the bacteria to spread through the body unchecked by the immune system, resulting in rapid and potentially lethal anthrax infection.
When the bacterium (B. anthracis) is inhaled, its spores are surrounded by alveolar macrophages in the lung, the beginning stage of normal immune response. But instead of succumbing to the defensive assault, they survive and germinate within the cells, traveling with the macrophages in their normal sentinel duty throughout the body to the lymph nodes, and eventually into the bloodstream, ultimately leading to fatal systemic shock if treatment fails.
Michael Karin, Ph.D.
In order to understand how anthrax was evading the immune system, the research team led by Michael Karin, Ph.D., UCSD professor of pharmacology and American Cancer Society Research Professor, used a variety of lab tests to determine how LT caused cell death in mouse macrophage cells. They pinpointed a series of steps, and specifically inhibition of an enzyme (a protein kinase) called p38, that lead to macrophage death and prevent secretion of chemokines and cytokines, the signaling agents that alert the immune system to the presence of an invading pathogen.
According to Karin, these findings open the door for development of an antidote that could block the action of a specific toxin called lethal factor (LF). Entering the macrophage with the aid of another B. anthracis protein called protective antigen (PA) which binds to the cell surface and allows bacterial proteins to penetrate the macrophage, LF cleaves and disables specific protein kinases (called mitogen activated protein kinase kinases, or MKKs) that play a vital role in activation of the p38 protein kinase, whose enzymatic activity is essential for survival of the macrophage. With the kinases knocked out, macrophage death ensues when encountering bacteria.
The devastating combination of LF and PA is the complex the researchers have labeled LT, or lethal toxin. Also secreting a third toxic protein called EF, or edema factor, that causes tissue edema, B. anthracis launches effective weaponry that essentially clears the way for successful invasion of the body without interference by the immune system.
|Mouse macrophage cells were exposed to anthrax and analyzed after 8 hours for destroyed macrophage.|
"If we are correct, inhibition of the toxin's activity should give our bodies enough time to detect an infection and fight it," Karin said.
He added that researchers have observed that with anthrax and other deadly pathogens, such as bubonic plague, it takes several days or up to a week for symptoms to appear, as the body's normal immune response has been subdued.
"We've wondered why this bug does not make patients sick early on, especially since it doesn't take many bacteria to make us sick," he said. "Feeling sick is actually good. It means we're fighting the effects of infection with a fever or runny nose. Not being sick means your immune system is not detecting the infection."
The Karin team is continuing research to determine the relevance of their findings in living animals. In their paper, the team suggests that future research should focus on the balance between macrophage activation and cell death, as it seems to play a key role in the pathogenesis of anthrax and other deadly infections.
The study was funded by the National Institutes of Health and the Superfund basic research program. In addition to Karin, additional team members were first author Jin Mo Park, Ph.D., and researchers Florian R. Greten, M.D. and Zhi-Wei Li, Ph.D., Laboratory of Gene Regulation and Signal Transduction, UCSD Department of Pharmacology.
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