title: Loss of the DNA Damage Repair Kinase ATM Impairs Inflammasome-Dependent Anti-Bacterial Innate Immunity.
abstract: The ATM kinase is a central component of the DNA damage repair machinery and redox balance. ATM dysfunction results in the multisystem disease ataxia-telangiectasia (AT). A major cause of mortality in AT is respiratory bacterial infections. Whether ATM deficiency causes innate immune defects that might contribute to bacterial infections is not known. Here we have shown that loss of ATM impairs inflammasome-dependent anti-bacterial innate immunity. Cells from AT patients or Atm(-/-) mice exhibited diminished interleukin-1β (IL-1β) production in response to bacteria. In vivo, Atm(-/-) mice were more susceptible to pulmonary S. pneumoniae infection in a manner consistent with inflammasome defects. Our data indicate that such defects were due to oxidative inhibition of inflammasome complex assembly. This study reveals an unanticipated function of reactive oxygen species (ROS) in negative regulation of inflammasomes and proposes a theory for the notable susceptibility of AT patients to pulmonary bacterial infection.
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå 901 87, Sweden; Department of Molecular Biology, Umeå University, Umeå 901 87, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå 901 87, Sweden.
authors.forename: Saskia F
authors.initials: SF
authors.lastname: Erttmann
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå 901 87, Sweden; Department of Molecular Biology, Umeå University, Umeå 901 87, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå 901 87, Sweden.
authors.forename: Anetta
authors.initials: A
authors.lastname: Härtlova
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå 901 87, Sweden; Department of Molecular Biology, Umeå University, Umeå 901 87, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå 901 87, Sweden.
authors.forename: Marta
authors.initials: M
authors.lastname: Sloniecka
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå 901 87, Sweden; Department of Molecular Biology, Umeå University, Umeå 901 87, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå 901 87, Sweden.
authors.forename: Faizal A M
authors.initials: FA
authors.lastname: Raffi
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå 901 87, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå 901 87, Sweden; Department of Clinical Microbiology, Umeå University, Umeå 901 87, Sweden.
authors.forename: Ava
authors.initials: A
authors.lastname: Hosseinzadeh
authors.affiliation: Department of Molecular Biology, Umeå University, Umeå 901 87, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå 901 87, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Edgren
authors.affiliation: Department of Biochemistry, Institute of Biochemistry and Biophysics, Tehran University, Tehran, Iran.
authors.forename: Reza
authors.initials: R
authors.lastname: Rofougaran
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå 901 87, Sweden; Department of Molecular Biology, Umeå University, Umeå 901 87, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå 901 87, Sweden.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Resch
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå 901 87, Sweden; Department of Molecular Biology, Umeå University, Umeå 901 87, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå 901 87, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Fällman
authors.affiliation: Department of Paediatrics, Hospital of Halland, 30185 Halmstad, Sweden.
authors.forename: Torben
authors.initials: T
authors.lastname: Ek
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå 901 87, Sweden; Department of Molecular Biology, Umeå University, Umeå 901 87, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå 901 87, Sweden. Electronic address: nelson.gekara@mims.umu.se.
authors.forename: Nelson O
authors.initials: NO
authors.lastname: Gekara
mesh_terms: D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000502:physiology; D053583:Interleukin-1beta; D008168:Lung / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D011008:Pneumococcal Infections / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000276:immunology*
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse