Anthrax Invades and Evades the Immune System to Cause Widespread Infection

Michael Karin
University of California, San Diego
R37ES04151, R01ES06376, and P42ES10337

Background: The popular press has been filled with reports of anthrax exposure since September 11th. Usually a disease that strikes mostly livestock and wild animals, it has become a household word since its use as a weapon of terror. The most severe form of the disease results from inhalation of Bacillus anthracis spores which are engulfed or phagocytised by macrophages in the lung. Phagocytosis of bacteria by macrophages is a normal and effective method of the innate immune system to fight the spread of infection. However, in the case of anthrax, the bacteria survive phagocytosis, reproduce within the cells, and use the macrophages as a transport mechanism to invade lymph nodes and eventually the blood stream leading to widespread infection, disease, and death. Until now, the mechanisms by which B. anthracis kills macrophages and avoids detection by the host immune system has been unclear.

Advance: NIEHS supported researchers at the University of California at San Diego have discovered that B. anthracis evades the host immune system, using a toxin called lethal factor (LF) to destroy macrophages and spread throughout the body. Apparently LF cleaves a mitogen activated kinase (MAPK) kinase that activates p38 MAPK by a cellular process known as phosphorylation. If p38 is not activated inside the macrophage the cell dies by apoptosis rather than proliferating. This is quite common in the immune system; if a cell doesn't get all the right signals for proliferation it dies. Since the macrophages do not proliferate, their ability to secrete the signaling agents that rev up the immune system is greatly reduced and thus the natural immune system does not mount the necessary defense to fight the infection. The investigators speculate that many other pathogenic bacteria probably use this approach.

Implication: These results may explain why anthrax infections proceed nearly undetected until the patient is very sick and near death. Since the cascade of events leading to infection is now clearer, this research may clear a path to the discovery of a drug or agent to block the action of LF and therefore, give the immune system, and other therapeutic agents, more time to detect the infection and fight it. Future research by these investigators will focus on the intricate balance of macrophage activation and death since it seems to play a key role in the ability of the bacteria to spread, multiply, and set up a deadly systemic infection.

Citation: Macrophage Apoptosis by Anthrax Lethal Factor Through p38 MAP Kinase Inhibition Jin Mo Park, Florian R. Greten, Zhi-Wei Li, and Michael Karin. Published online August 29 2002; 10.1126/Science.1073163