Sep 12, 2002 (CIDRAP News) Researchers report they have discovered the probable strategy that anthrax uses to kill macrophages, a step that may allow the pathogen to escape detection by the innate immune system.
Michael Karin and colleagues at the University of California, San Diego, say that a Bacillus anthracis protein disrupts an enzyme pathway that appears to be essential for preventing apoptosis, or programmed death, of activated macrophages. That prevents macrophages from sending chemical messengers to warn the rest of the immune system of the invaders. Their report was published recently in Sciencexpress, the online edition of Science.
Macrophages in the alveoli of the lungs engulf invading anthrax spores, the report notes. Normally macrophages kill invading bacteria and send warning signals to the rest of the immune system. But anthrax spores survive and germinate in the macrophages and travel with them to lymph nodes, and eventually the bacteria spread into the bloodstream.
The researchers determined that B anthracis lethal factor (LF), one of three proteins central to anthrax's toxicity, disables an enzyme that activates another enzyme called p38 MAPK (mitogen-activated protein kinase). The authors suggest that p38 MAPK normally works with another enzyme, NF-kappaB (nuclear factor kappaB), to trigger the expression of genes that produce a factor that inhibits apoptosis.
"By inhibiting activation of p38 MAPK, this deadly pathogen switches the signal for macrophage activation to a trigger of rapid cell death," the report states. "Selective killing of activated macrophages prevents the secretion of chemokines and cytokines that alert the remainder of the immune system to the presence of the pathogen. This may explain why anthrax infections proceed undetected until the terminal stage, when vast bacteremia occurs."
The authors conclude that future research "should focus on the balance between macrophage activation and apoptosis," which seems to play a key role in the pathogenesis of anthrax.
Park JM, Greten FR, Li Z, et al. Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Sciencexpress 2002 Aug 29 (early online publication)
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