title: Anthrax lethal toxin impairs innate immune functions of alveolar macrophages and facilitates Bacillus anthracis survival.
abstract: Alveolar macrophages (AM) are very important for pulmonary innate immune responses against invading inhaled pathogens because they directly kill the organisms and initiate a cascade of innate and adaptive immune responses. Although several factors contribute to inhalational anthrax, we hypothesized that unimpeded infection of Bacillus anthracis is directly linked to disabling the innate immune functions contributed by AM. Here, we investigated the effects of lethal toxin (LT), one of the binary complex virulence factors produced by B. anthracis, on freshly isolated nonhuman primate AM. Exposure of AM to doses of LT that killed susceptible macrophages had no effect on the viability of AM, despite complete MEK1 cleavage. Intoxicated AM remained fully capable of B. anthracis spore phagocytosis. However, pretreatment of AM with LT resulted in a significant decrease in the clearance of both the Sterne strain and the fully virulent Ames strain of B. anthracis, which may have been a result of impaired AM secretion of proinflammatory cytokines. Our data imply that cytolysis does not correlate with MEK1 cleavage, and this is the first report of LT-mediated impairment of nonhuman primate AM bactericidal activity against B. anthracis.
authors.affiliation: Target Identification and Translational Research, U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, MD 21702-5011, USA.
authors.forename: Wilson J
authors.initials: WJ
authors.lastname: Ribot
authors.forename: Rekha G
authors.initials: RG
authors.lastname: Panchal
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Brittingham
authors.forename: Gordon
authors.initials: G
authors.lastname: Ruthel
authors.forename: Tara A
authors.initials: TA
authors.lastname: Kenny
authors.forename: Douglas
authors.initials: D
authors.lastname: Lane
authors.forename: Bob
authors.initials: B
authors.lastname: Curry
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hoover
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Friedlander
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
mesh_terms: D000818:Animals; D000881:Anthrax / Q000382:microbiology*; D000942:Antigens, Bacterial / Q000494:pharmacology*; D001408:Bacillus anthracis / Q000472:pathogenicity* / Q000502:physiology; D001427:Bacterial Toxins / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008252:Macaca fascicularis; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects*
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D016207:Cytokines; C030325:anthrax toxin; D048369:MAP Kinase Kinase 1