title: NAIP and Ipaf control Legionella pneumophila replication in human cells.
abstract: In mice, different alleles of the mNAIP5 (murine neuronal apoptosis inhibitory protein-5)/mBirc1e gene determine whether macrophages restrict or support intracellular replication of Legionella pneumophila, and whether a mouse is resistant or (moderately) susceptible to Legionella infection. In the resistant mice strains, the nucleotide-binding oligomerization domain (Nod)-like receptor (NLR) family member mNAIP5/mBirc1e, as well as the NLR protein mIpaf (murine ICE protease-activating factor), are involved in recognition of Legionella flagellin and in restriction of bacterial replication. Human macrophages and lung epithelial cells support L. pneumophila growth, and humans can develop severe pneumonia (Legionnaires disease) after Legionella infection. The role of human orthologs to mNAIP5/mBirc1e and mIpaf in this bacterial infection has not been elucidated. Herein we demonstrate that flagellin-deficient L. pneumophila replicate more efficiently in human THP-1 macrophages, primary monocyte-derived macrophages, and alveolar macrophages, and in A549 lung epithelial cells compared with wild-type bacteria. Additionally, we note expression of the mNAIP5 ortholog hNAIP in all cell types examined, and expression of hIpaf in human macrophages. Gene silencing of hNAIP or hIpaf in macrophages or of hNAIP in lung epithelial cells leads to an enhanced bacterial growth, and overexpression of both molecules strongly reduces Legionella replication. In contrast to experiments with wild-type L. pneumophila, hNAIP or hIpaf knock-down affects the (enhanced) replication of flagellin-deficient Legionella only marginally. In conclusion, hNAIP and hIpaf mediate innate intracellular defense against flagellated Legionella in human cells.
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Maya
authors.initials: M
authors.lastname: Vinzing
authors.forename: Julia
authors.initials: J
authors.lastname: Eitel
authors.forename: Juliane
authors.initials: J
authors.lastname: Lippmann
authors.forename: Andreas C
authors.initials: AC
authors.lastname: Hocke
authors.forename: Janine
authors.initials: J
authors.lastname: Zahlten
authors.forename: Hortense
authors.initials: H
authors.lastname: Slevogt
authors.forename: Philippe Dje
authors.initials: PD
authors.lastname: N'guessan
authors.forename: Stefan
authors.initials: S
authors.lastname: Günther
authors.forename: Bernd
authors.initials: B
authors.lastname: Schmeck
authors.forename: Stefan
authors.initials: S
authors.lastname: Hippenstiel
authors.forename: Antje
authors.initials: A
authors.lastname: Flieger
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.forename: Bastian
authors.initials: B
authors.lastname: Opitz
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D015153:Blotting, Western; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D005408:Flagellin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D016952:Legionella pneumophila / Q000254:growth & development*; D007877:Legionnaires' Disease / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D018613:Microscopy, Confocal; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; C496800:NAIP protein, human; C435692:NLRC4 protein, human; D051616:Neuronal Apoptosis-Inhibitory Protein; D005408:Flagellin