Protective antigen

Bacillus anthracis is a gram-positive, spore-forming, encapsulated, non-motile rod. Its virulence depends on two plasmids: pXO1 encodes the tripartite toxin (PA, LF, EF) and pXO2 encodes the poly-D-glutamic acid capsule, which is antiphagocytic. The toxin follows an A-B model in which PA is the B (binding/translocation) component and LF and EF are the A (enzymatic) components. Mechanism: (1) PA83 binds ANTXR1 (TEM8) or ANTXR2 (CMG2) on the host cell surface. (2) Host furin or a furin-like protease cleaves PA83 to PA63, releasing the 20-kDa fragment. (3) PA63 oligomerizes into a heptameric or octameric prepore that binds LF and/or EF. (4) The complex is endocytosed, and acidification of the endosome converts the prepore to a pore. (5) LF and EF are translocated into the cytosol. Enzymatic effects: Lethal factor is a zinc metalloprotease that cleaves MAP kinase kinases (MEKs), disrupting signaling and causing cell death, immune suppression, and shock. Edema factor is a calmodulin-dependent adenylate cyclase that raises cAMP, causing tissue edema and impaired neutrophil function. Lethal toxin = PA + LF; edema toxin = PA + EF. PA alone is nontoxic. Clinical forms: cutaneous anthrax (most common, painless black eschar with edema, from spore contact with broken skin), inhalational anthrax (woolsorter's disease; spores are carried by macrophages to mediastinal lymph nodes, causing hemorrhagic mediastinitis with widened mediastinum on CXR, hemorrhagic pleural effusions, and rapid progression to shock; high mortality), gastrointestinal anthrax (from undercooked meat), and injection anthrax (in heroin users). Hemorrhagic meningitis can complicate any form. Diagnosis: gram-positive rods in chains (boxcar appearance) on Gram stain, non-hemolytic colonies on blood agar with a 'medusa head' appearance, and PCR. Treatment: ciprofloxacin or doxycycline, often combined with additional agents such as clindamycin or linezolid (to inhibit toxin synthesis) for systemic disease, plus antitoxin (raxibacumab or obiltoxaximab, monoclonal antibodies that bind PA and block receptor binding; anthrax immune globulin is also available). Prophylaxis: ciprofloxacin or doxycycline after exposure, plus vaccination. Vaccine: BioThrax (AVA) and the newer Cyfendus (AV7909) are cell-free vaccines whose main immunogen is PA. They are given to military personnel, laboratory workers, and persons at high occupational risk. Anti-PA neutralizing antibodies correlate with protection, hence the name 'protective' antigen. High-yield: PA is the common binding component of both toxins; LF = MEK protease; EF = adenylate cyclase (compare with cholera toxin, pertussis toxin, and Bordetella adenylate cyclase toxin, which also raise cAMP). Anthrax is a Category A bioterrorism agent. B. anthracis is also unusual among bacteria in having a polypeptide (D-glutamate) capsule instead of a polysaccharide capsule.