title: Generation of a Listeria vaccine strain by enhanced caspase-1 activation.
abstract: The immunostimulatory properties conferred by vaccine adjuvants require caspase-1 for processing of IL-1β and IL-18. Caspase-1 is activated in response to a breach of the cytosolic compartment by microbes and the process is initiated by intracellular pattern recognition receptors within inflammasomes. Listeria monocytogenes is detected in the cytosol by the NLRC4, NLRP3 and AIM2 inflammasomes. NLRC4 is activated by flagellin, and L. monocytogenes evades NLRC4 by repressing flagellin expression. We generated an L. monocytogenes strain that was forced to express flagellin in the host cell cytosol. This strain hyperactivated caspase-1 and was preferentially cleared via NLRC4 detection in an IL-1β/IL-18 independent manner. We also created a strain of L. monocytogenes with forced expression of another NLRC4 agonist, PrgJ, from the Type III secretion system of Salmonella typhimurium. Forced expression of flagellin or PrgJ resulted in attenuation, yet both strains conferred protective immunity in mice against lethal challenge with L. monocytogenes. This work is the first demonstration of specific targeting of the caspase-1 activation pathway to generate a safe and potent L. monocytogenes-based vaccine. Moreover, the attenuated strains with embedded flagellin or PrgJ adjuvants represent attractive vectors for vaccines aimed at eliciting T-cell responses.
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Warren
authors.forename: Hien
authors.initials: H
authors.lastname: Duong
authors.forename: Dat Phat
authors.initials: DP
authors.lastname: Mao
authors.forename: Abraham
authors.initials: A
authors.lastname: Armstrong
authors.forename: Jayant
authors.initials: J
authors.lastname: Rajan
authors.forename: Edward A
authors.initials: EA
authors.lastname: Miao
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D058947:Bacterial Secretion Systems / Q000235:genetics; D001428:Bacterial Vaccines / Q000276:immunology; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D002478:Cells, Cultured; D005408:Flagellin / Q000276:immunology; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008089:Listeria monocytogenes / Q000276:immunology* / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012486:Salmonella typhimurium / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins; D058947:Bacterial Secretion Systems; D001428:Bacterial Vaccines; D002135:Calcium-Binding Proteins; D020382:Interleukin-18; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D005408:Flagellin; D020170:Caspase 1