Inhalational
anthrax is caused by inhalation of Bacillus anthracis spores. The ability of B. anthracis to cause
anthrax is attributed to the plasmid-encoded A/B-type toxins,
edema toxin (
edema factor and protective
antigen) and lethal toxin (lethal factor and protective
antigen), and a poly-d-
glutamic acid capsule. To better understand the contribution of these toxins to the disease pathophysiology in vivo, we used B. anthracis Ames strain and isogenic toxin deletion mutants derived from the Ames strain to examine the role of lethal toxin and
edema toxin after pulmonary spore challenge of cynomolgus macaques. Lethal toxin, but not
edema toxin, was required to induce sustained
bacteremia and death after pulmonary challenge with spores delivered via bronchoscopy. After intravenous challenge with bacilli to model the systemic phase of
infection, lethal toxin contributed to bacterial proliferation and subsequent host death to a greater extent than
edema toxin. Deletion of protective
antigen resulted in greater loss of virulence after intravenous challenge with bacilli than deletion of lethal toxin or
edema toxin alone. These findings are consistent with the ability of anti-protective
antigen antibodies to prevent
anthrax and suggest that lethal factor is the dominant toxin that contributes to the escape of significant numbers of bacilli from the thoracic cavity to cause
anthrax after inhalation challenge with spores.