Anthrax

The causative agent of anthrax is the spore-forming bacterium, Bacillus anthracis, which is considered a major bioterrorism threat because its spores are very stable, easily disseminated, and infectious by aerosol. The clinical form of the disease is dependent on the route of exposure and can manifest as cutaneous, gastrointestinal, or inhalational anthrax. Irrespective of the route acquired, septic anthrax is a devastating infection with high mortality. The virulence of B. anthracis is dependent on the production of an antiphagocytic capsule and two bipartite, proteinaceous toxins: lethal toxin and edema toxin. The toxins comprised three proteins, lethal factor (LF), edema factor (EF), and protective antigen (PA). PA, the binding moiety of each toxin, facilitates toxin entry into host cells. LF, the enzymatic portion of lethal toxin, is a zinc metalloprotease that cleaves the N-terminal region of mitogen-activated kinase kinases. This toxin interferes with the function of host immune cells and disrupts the endothelial barrier. EF, the enzymatic moiety of edema toxin, is a calmodulin-dependent adenylyl cyclase that converts ATP to cAMP, resulting in immune cell dysfunction and tissue edema. The pathology associated with an anthrax infection (i.e., hemorrhage, necrosis, and edema) is the result of the action of the toxins. The current FDA-licensed anthrax vaccine comprised filter-sterilized culture media, in which an attenuated (capsule-deficient) strain of B. anthracis has grown, combined with aluminum hydroxide adjuvant. While all secreted or released bacterial proteins are present in the vaccine formulation, the major immunogen is PA. The levels of antibodies to PA elicited by the vaccine directly correlate with survival in infected animal models. The need for a chemically defined vaccine has led to the development of a second-generation vaccine, consisting of recombinant PA and the aluminum hydroxide adjuvant. This new vaccine has proved efficacious in the nonhuman primate and rabbit models of inhalation anthrax, and clinical trials are currently evaluating the safety and immunogenicity in human volunteers. Apart from active immunization, passive transfer of antibodies to PA is efficacious in anthrax animal models. Compounds that inhibit the action of the toxins are also being investigated. These recent advances have increased the arsenal of therapeutics that can be used in the future to improve the prognosis of anthrax-infected individuals.