title: Lethal factor, but not edema factor, is required to cause fatal anthrax in cynomolgus macaques after pulmonary spore challenge.
abstract: 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.
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, New Mexico; Center for Infectious Disease & Immunity, University of New Mexico Health Science Center, Albuquerque, New Mexico. Electronic address: jhutt@lrri.org.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Hutt
authors.affiliation: Center for Infectious Disease & Immunity, University of New Mexico Health Science Center, Albuquerque, New Mexico; Department of Internal Medicine, University of New Mexico Health Science Center, Albuquerque, New Mexico.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lovchik
authors.affiliation: Center for Infectious Disease & Immunity, University of New Mexico Health Science Center, Albuquerque, New Mexico; Department of Internal Medicine, University of New Mexico Health Science Center, Albuquerque, New Mexico.
authors.forename: Melissa
authors.initials: M
authors.lastname: Drysdale
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sherwood
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Trevor
authors.initials: T
authors.lastname: Brasel
authors.affiliation: Department of Pathology, University of New Mexico Health Science Center, Albuquerque, New Mexico.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Lipscomb
authors.affiliation: Center for Infectious Disease & Immunity, University of New Mexico Health Science Center, Albuquerque, New Mexico; Department of Internal Medicine, University of New Mexico Health Science Center, Albuquerque, New Mexico.
authors.forename: C Rick
authors.initials: CR
authors.lastname: Lyons
mesh_terms: D000818:Animals; D000881:Anthrax / Q000382:microbiology*; D000907:Antibodies, Bacterial / Q000097:blood; D000942:Antigens, Bacterial / Q000378:metabolism*; D001408:Bacillus anthracis / Q000472:pathogenicity*; D001427:Bacterial Toxins / Q000378:metabolism*; D005260:Female; D008168:Lung / Q000382:microbiology*; D008251:Macaca; D008297:Male; D012141:Respiratory Tract Infections / Q000382:microbiology*; D013171:Spores, Bacterial / Q000472:pathogenicity; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D037521:Virulence Factors; C030325:anthrax toxin