title: Legionella pneumophilaStrain 130b Evades Macrophage Cell Death Independent of the Effector SidF in the Absence of Flagellin.
abstract: The human pathogenLegionella pneumophilamust evade host cell death signaling to enable replication in lung macrophages and to cause disease. After bacterial growth, however,L. pneumophilais thought to induce apoptosis during egress from macrophages. The bacterial effector protein, SidF, has been shown to control host cell survival and death by inhibiting pro-apoptotic BNIP3 and BCL-RAMBO signaling. Using live-cell imaging to follow theL. pneumophila-macrophage interaction, we now demonstrate thatL. pneumophilaevades host cell apoptosis independent of SidF. In the absence of SidF,L. pneumophilawas able to replicate, cause loss of mitochondria membrane potential, kill macrophages, and establish infections in lungs of mice. Consistent with this, deletion of BNIP3 and BCL-RAMBO did not affect intracellularL. pneumophilareplication, macrophage death rates, andin vivobacterial virulence. Abrogating mitochondrial cell death by genetic deletion of the effectors of intrinsic apoptosis, BAX, and BAK, or the regulator of mitochondrial permeability transition pore formation, cyclophilin-D, did not affect bacterial growth or the initial killing of macrophages. Loss of BAX and BAK only marginally limited the ability ofL. pneumophilato efficiently kill all macrophages over extended periods.L. pneumophilainduced killing of macrophages was delayed in the absence of capsase-11 mediated pyroptosis. Together, our data demonstrate thatL. pneumophilaevades host cell death responses independently of SidF during replication and can induce pyroptosis to kill macrophages in a timely manner.
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University Clayton, VIC, Australia.
authors.forename: Mary
authors.initials: M
authors.lastname: Speir
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University Clayton, VIC, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: Vogrin
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University Clayton, VIC, Australia.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Seidi
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University Clayton, VIC, Australia.
authors.forename: Gilu
authors.initials: G
authors.lastname: Abraham
authors.affiliation: Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of MedicineNew Haven, CT, USA; Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut du Cerveau et la Moelle - Hôpital Pitié-Salpêtrière, Boulevard de l'hôpital, Sorbonne Universités, UPMC Univ Paris 06Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Hunot
authors.affiliation: Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine New Haven, CT, USA.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Han
authors.affiliation: Department of Medicine, Center for Pharmacogenomics, Washington University School of Medicine St. Louis, MO, USA.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.affiliation: Walter and Eliza Hall Institute of Medical ResearchParkville, VIC, Australia; Department of Medical Biology, University of MelbourneParkville, VIC, Australia.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
authors.affiliation: Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine New Haven, CT, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Walter and Eliza Hall Institute of Medical ResearchParkville, VIC, Australia; Department of Medical Biology, University of MelbourneParkville, VIC, Australia.
authors.forename: James E
authors.initials: JE
authors.lastname: Vince
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University Clayton, VIC, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Naderer
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death; D002470:Cell Survival; D005260:Female; D005408:Flagellin / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D054884:Host-Pathogen Interactions; D016952:Legionella pneumophila / Q000502:physiology*; D007877:Legionnaires' Disease / Q000378:metabolism / Q000382:microbiology*; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C508686:BNip3 protein, mouse; D001426:Bacterial Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D037521:Virulence Factors; D005408:Flagellin
keywords: bacteria; caspases; infection; live-cell imaging; mitochondria; pneumonia; pyroptosis