title: Circulating lethal toxin decreases the ability of neutrophils to respond to Bacillus anthracis.
abstract: Polymorphonuclear leucocytes (PMNs) play a protective role during Bacillus anthracis infection. However, B. anthracis is able to subvert the PMN response effectively as evidenced by the high mortality rates of anthrax. One major virulence factor produced by B. anthracis, lethal toxin (LT), is necessary for dissemination in the BSL2 model of mouse infection. While human and mouse PMNs kill vegetative B. anthracis, short in vitro half-lives of PMNs have made it difficult to determine how or if LT alters their bactericidal function. Additionally, the role of LT intoxication on PMN's ability to migrate to inflammatory signals remains controversial. LF concentrations in both serum and major organs were determined from mice infected with B. anthracis Sterne strain at defined stages of infection to guide subsequent administration of purified toxin. Bactericidal activity of PMNs assessed using ex vivo cell culture assays showed significant defects in killing B. anthracis. In vivo PMN recruitment to inflammatory stimuli was significantly impaired at 24 h as assessed by real-time analysis of light-producing PMNs within the mouse. The observations described above suggest that LT serves dual functions; it both attenuates accumulation of PMNs at sites of inflammation and impairs PMNs bactericidal activity against vegetative B. anthracis.
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Zachary P
authors.initials: ZP
authors.lastname: Weiner
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ernst
authors.forename: Anne E
authors.initials: AE
authors.lastname: Boyer
authors.forename: Maribel
authors.initials: M
authors.lastname: Gallegos-Candela
authors.forename: John R
authors.initials: JR
authors.lastname: Barr
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Glomski
mesh_terms: D000825:Animal Structures / Q000737:chemistry; D000818:Animals; D000881:Anthrax / Q000276:immunology / Q000382:microbiology; D000942:Antigens, Bacterial / Q000032:analysis / Q000276:immunology* / Q000633:toxicity*; D001408:Bacillus anthracis / Q000276:immunology*; D001427:Bacterial Toxins / Q000032:analysis / Q000276:immunology* / Q000633:toxicity*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology*; D044967:Serum / Q000737:chemistry
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin