title: Edema toxin impairs anthracidal phospholipase A2 expression by alveolar macrophages.
abstract: Bacillus anthracis, the etiological agent of anthrax, is a spore-forming gram-positive bacterium. Infection with this pathogen results in multisystem dysfunction and death. The pathogenicity of B. anthracis is due to the production of virulence factors, including edema toxin (ET). Recently, we established the protective role of type-IIA secreted phospholipase A2 (sPLA2-IIA) against B. anthracis. A component of innate immunity produced by alveolar macrophages (AMs), sPLA2-IIA is found in human and animal bronchoalveolar lavages at sufficient levels to kill B. anthracis. However, pulmonary anthrax is almost always fatal, suggesting the potential impairment of sPLA2-IIA synthesis and/or action by B. anthracis factors. We investigated the effect of purified ET and ET-deficient B. anthracis strains on sPLA2-IIA expression in primary guinea pig AMs. We report that ET inhibits sPLA2-IIA expression in AMs at the transcriptional level via a cAMP/protein kinase A-dependent process. Moreover, we show that live B. anthracis strains expressing functional ET inhibit sPLA2-IIA expression, whereas ET-deficient strains induced this expression. This stimulatory effect, mediated partly by the cell wall peptidoglycan, can be counterbalanced by ET. We conclude that B. anthracis down-regulates sPLA2-IIA expression in AMs through a process involving ET. Our study, therefore, describes a new molecular mechanism implemented by B. anthracis to escape innate host defense. These pioneering data will provide new molecular targets for future intervention against this deadly pathogen.
authors: Institut Pasteur, Unité de Défense Innée et Inflammation, Paris, France.
authors: Benoit
authors: B
authors: Raymond
authors: Dominique
authors: D
authors: Leduc
authors: Lucas
authors: L
authors: Ravaux
authors: Ronan
authors: R
authors: Le Goffic
authors: Thomas
authors: T
authors: Candela
authors: Michel
authors: M
authors: Raymondjean
authors: Pierre Louis
authors: PL
authors: Goossens
authors: Lhousseine
authors: L
authors: Touqui
mesh_terms: D000818:Animals; D000881:Anthrax / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D000942:Antigens, Bacterial / Q000633:toxicity*; D001408:Bacillus anthracis / Q000201:enzymology*; D001427:Bacterial Toxins / Q000633:toxicity*; D018893:Bronchoalveolar Lavage; D002478:Cells, Cultured; D015536:Down-Regulation; D015964:Gene Expression Regulation, Bacterial; D020868:Gene Silencing; D054501:Group II Phospholipases A2 / Q000276:immunology / Q000378:metabolism*; D006168:Guinea Pigs; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000201:enzymology / Q000382:microbiology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D012333:RNA, Messenger; C030325:anthrax toxin; D054501:Group II Phospholipases A2