title: Listeria monocytogenes engineered to activate the Nlrc4 inflammasome are severely attenuated and are poor inducers of protective immunity.
abstract: Inflammasomes are intracellular multiprotein signaling complexes that activate Caspase-1, leading to the cleavage and secretion of IL-1β and IL-18, and ultimately host cell death. Inflammasome activation is a common cellular response to infection; however, the consequences of inflammasome activation during acute infection and in the development of long-term protective immunity is not well understood. To investigate the role of the inflammasome in vivo, we engineered a strain of Listeria monocytogenes that ectopically expresses Legionella pneumophila flagellin, a potent activator of the Nlrc4 inflammasome. Compared with wild-type L. monocytogenes, strains that ectopically secreted flagellin induced robust host cell death and IL-1β secretion. These strains were highly attenuated both in bone marrow-derived macrophages and in vivo compared with wild-type L. monocytogenes. Attenuation in vivo was dependent on Nlrc4, but independent of IL-1β/IL-18 or neutrophil activity. L. monocytogenes strains that activated the inflammasome generated significantly less protective immunity, a phenotype that correlated with decreased induction of antigen-specific T cells. Our data suggest that avoidance of inflammasome activation is a critical virulence strategy for intracellular pathogens, and that activation of the inflammasome leads to decreased long-term protective immunity and diminished T-cell responses.
authors: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3202, USA.
authors: John-Demian
authors: JD
authors: Sauer
authors: Sabine
authors: S
authors: Pereyre
authors: Kristina A
authors: KA
authors: Archer
authors: Thomas P
authors: TP
authors: Burke
authors: Bill
authors: B
authors: Hanson
authors: Peter
authors: P
authors: Lauer
authors: Daniel A
authors: DA
authors: Portnoy
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology*; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology*; D003598:Cytoskeletal Proteins / Q000276:immunology; D005260:Female; D005408:Flagellin / Q000235:genetics / Q000276:immunology; D005818:Genetic Engineering; D054884:Host-Pathogen Interactions / Q000276:immunology; D007111:Immunity, Cellular; D007113:Immunity, Innate; D007114:Immunization; D058847:Inflammasomes / Q000235:genetics* / Q000276:immunology*; D016952:Legionella pneumophila / Q000235:genetics / Q000276:immunology; D008089:Listeria monocytogenes / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D008088:Listeriosis / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014774:Virulence / Q000235:genetics / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; C512299:Ipaf protein, mouse; C498534:Pycard protein, mouse; D005408:Flagellin