title: Inhibition of inflammasome activation by Coxiella burnetii type IV secretion system effector IcaA.
abstract: Coxiella burnetii is a highly infectious bacterium that promotes its own replication in macrophages by inhibiting several host cell responses. Here, we show that C. burnetii inhibits caspase-1 activation in primary mouse macrophages. By using co-infection experiments, we determine that the infection of macrophages with C. burnetii inhibits the caspase-11-mediated non-canonical activation of the NLRP3 inflammasome induced by subsequent infection with Escherichia coli or Legionella pneumophila. Genetic screening using flagellin mutants of L. pneumophila as a surrogate host, reveals a novel C. burnetii gene (IcaA) involved in the inhibition of caspase activation. Expression of IcaA in L. pneumophila inhibited the caspase-11 activation in macrophages. Moreover, icaA(-) mutants of C. burnetii failed to suppress the caspase-11-mediated inflammasome activation induced by L. pneumophila. Our data reveal IcaA as a novel C. burnetii effector protein that is secreted by the Dot/Icm type IV secretion system and interferes with the caspase-11-induced, non-canonical activation of the inflammasome.
authors.affiliation: Department of Cell Biology, Medical School of Ribeirão Preto, University of São Paulo (FMRP/USP), Ribeirão Preto, Sao Paulo 14049-900, Brazil.
authors.forename: Larissa D
authors.initials: LD
authors.lastname: Cunha
authors.affiliation: Department of Cell Biology, Medical School of Ribeirão Preto, University of São Paulo (FMRP/USP), Ribeirão Preto, Sao Paulo 14049-900, Brazil.
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Ribeiro
authors.affiliation: Department of Cell Biology, Medical School of Ribeirão Preto, University of São Paulo (FMRP/USP), Ribeirão Preto, Sao Paulo 14049-900, Brazil.
authors.forename: Talita D
authors.initials: TD
authors.lastname: Fernandes
authors.affiliation: Department of Cell Biology, Medical School of Ribeirão Preto, University of São Paulo (FMRP/USP), Ribeirão Preto, Sao Paulo 14049-900, Brazil.
authors.forename: Liliana M
authors.initials: LM
authors.lastname: Massis
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia.
authors.forename: Chen Ai
authors.initials: CA
authors.lastname: Khoo
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Moffatt
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia.
authors.forename: Hayley J
authors.initials: HJ
authors.lastname: Newton
authors.affiliation: Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Roy
authors.affiliation: Department of Cell Biology, Medical School of Ribeirão Preto, University of São Paulo (FMRP/USP), Ribeirão Preto, Sao Paulo 14049-900, Brazil.
authors.forename: Dario S
authors.initials: DS
authors.lastname: Zamboni
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D020169:Caspases / Q000235:genetics / Q000276:immunology; D053471:Caspases, Initiator; D016997:Coxiella burnetii / Q000235:genetics / Q000276:immunology*; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011778:Q Fever / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D000069319:Type IV Secretion Systems / Q000235:genetics / Q000276:immunology*
chemical_list: D001426:Bacterial Proteins; D058847:Inflammasomes; D000069319:Type IV Secretion Systems; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator