title: Anthrax toxin induces macrophage death by p38 MAPK inhibition but leads to inflammasome activation via ATP leakage.
abstract: Detection of microbial constituents by membrane associated and cytoplasmic pattern recognition receptors is the essence of innate immunity, leading to activation of protective host responses. However, it is still unclear how immune cells specifically respond to pathogenic bacteria. Using virulent and nonvirulent strains of Bacillus anthracis, we have shown that secretion of ATP by infected macrophages and the sequential activation of the P2X7 purinergic receptor and nucleotide binding oligomerization domain (NOD)-like receptors are critical for IL-1-dependent host protection from virulent B. anthracis. Importantly, lethal toxin produced by virulent B. anthracis blocked activation of protein kinases, p38 MAPK and AKT, resulting in opening of a connexin ATP release channel and induction of macrophage death. Prevention of cell death or ATP release through constitutive p38 or AKT activation interfered with inflammasome activation and IL-1β production, thereby compromising antimicrobial immunity.
authors.affiliation: Laboratory of Signal Transduction, Department of Pharmacology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Syed Raza
authors.initials: SR
authors.lastname: Ali
authors.forename: Anjuli M
authors.initials: AM
authors.lastname: Timmer
authors.forename: Sameera
authors.initials: S
authors.lastname: Bilgrami
authors.forename: Eek Joong
authors.initials: EJ
authors.lastname: Park
authors.forename: Lars
authors.initials: L
authors.lastname: Eckmann
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000881:Anthrax / Q000276:immunology* / Q000382:microbiology; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001408:Bacillus anthracis / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism; D007113:Immunity, Innate / Q000235:genetics; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D014774:Virulence / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000942:Antigens, Bacterial; D051017:Apoptosis Regulatory Proteins; D001427:Bacterial Toxins; D018031:Connexin 43; D058847:Inflammasomes; D053583:Interleukin-1beta; C529636:NALP1 protein, mouse; D058486:Receptors, Purinergic P2X7; C030325:anthrax toxin; D000255:Adenosine Triphosphate; D051058:Oncogene Protein v-akt; D048051:p38 Mitogen-Activated Protein Kinases