Fighting anthrax with flies.

A nthrax is an infectious disease caused by the spore-forming bacterium Bacillus anthracis (1, 2). The endospores of the bacterium are remarkably resistant to physical stress and highly infectious (2). In October 2001, the attacks on the World Trade Center were followed by an outbreak of anthrax in the United States after the intentional release of spores through contaminated letters, leading to widespread panic and, eventually, the deaths of five people (1). These cases intensified the fight against the disease and prompted a more thorough examination of the mechanisms underlying the pathogenicity of threatening organisms, such as B. anthracis. In this issue of PNAS, Guichard et al. (3) observe that anthrax toxicity factors in Drosophila melanogaster act against similar cellular targets as those that have been identified in mammals, indicating that Drosophila may help fight disease and terror. The major challenge that is posed by anthrax is that the symptoms cannot be easily distinguished from influenza-like illness. Therefore, critical time might pass before an effective treatment can be applied. The anthrax toxicity results from the activity of three secreted polypeptides, the protective antigen (PA), lethal factor (LF), and edema factor (EF) (1, 2, 4). The PA binds to specific receptors on the surface of target cells. After its proteolytic processing, it polymerizes to form a heptameric pore in the membrane, facilitating binding and translocation of the enzymatically active LF and EF toxins within the target cell (1, 2, 4). LF is a Zn2 metalloprotease that has been shown to cleave six of the seven known human mitogen-activated protein kinase kinases (MAPKKs) in their proline-rich regulatory domain. As a result, MAPKKs are unable to bind, phosphorylate and subsequently activate their substrates, the downstream mitogen-activated protein kinases (MAPK) (1, 2, 4). EF is a Ca2 calmodulin-dependent adenylate cyclase (AC) that converts ATP into cAMP at a rate 1,000-fold higher than the rate of the endogenous AC enzyme (1, 2, 4).