Mouse Study Gives New View of Anthrax Toxin

WASHINGTON, D.C. -- A large-scale study of anthrax in mice has yielded new information about immune system response to anthrax bacteria, according to scientists at the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health. The discovery that toxins released by the bacteria do not behave as previously believed should redirect approaches to anthrax drug design, notes NIAID Senior Investigator Stephen Leppla, PhD, whose research is published in a recent issue of the Journal of Clinical Investigation.

In the new study, Leppla and his colleagues injected hundreds of inbred mice with anthrax lethal toxin (LT), and then took precisely timed measurements to determine how various organs and immune system processes responded. For example, they measured levels of chemicals called cytokines, which are released by immune system cells after a bacterial invasion. Leppla and his colleagues found no evidence of a persistent increase in cytokines, or of a link between cytokine increase and anthrax LT effects, contradicting earlier beliefs.

The evidence suggests that current efforts to design cytokine-suppressing drugs to treat lethal toxin-mediated events in late stages of anthrax may be misguided. "Finding effective therapies for diseases such as inhalational anthrax depends on our ability to connect basic research with clinicians' needs. This research is a perfect example of such translational research," says NIAID Director Anthony S. Fauci, MD.

"Science has had a good understanding of anthrax toxins at molecular and subcellular levels," says Leppla. "What has been lacking is a picture of the much more complex effects of toxins on tissues and animal models. Ours is one of the first comprehensive studies to critically examine what is actually happening at these higher levels of complexity."

In a natural infection, inhalational anthrax begins after anthrax bacteria spores enter the body, germinate and release toxins. Scientists can create artificial infection by injecting animals with anthrax LT. The accumulation of toxins precipitates events that lead to death. For more than a decade, scientists based their understanding of LT actions on the results of a few studies that employed a limited number of mice. Because of the high cost of doing anthrax toxin research and the small number of anthrax researchers, theories about LT action went largely unquestioned.

"We still do not know how LT brings about the hypoxia and shock-like death we see in mice," says the paper's first author, Mahtab Moayeri, PhD. The next important step, she adds, will be to identify the cell targets of LT and determine precisely how it initiates the chain of events leading to death.

Researchers at the National Cancer Institute also contributed to this research.

NIAID is a component of the National Institutes of Health (NIH), which is an agency of the Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.

Reference:

M Moayeri et al. Bacillus anthracis lethal toxin induces TNF-a independent hypoxia-mediated toxicity in mice. Journal of Clinical Investigation. 112:670-82 (2003) DOI: 10.1172/JCI 200317991.

Source: National Institutes of Health