title: NF-kappaB translocation prevents host cell death after low-dose challenge by Legionella pneumophila.
abstract: Legionella pneumophila, the causative agent of Legionnaires' disease, grows within macrophages and manipulates target cell signaling. Formation of a Legionella-containing replication vacuole requires the function of the bacterial type IV secretion system (Dot/Icm), which transfers protein substrates into the host cell cytoplasm. A global microarray analysis was used to examine the response of human macrophage-like U937 cells to low-dose infections with L. pneumophila. The most striking change in expression was the Dot/Icm-dependent up-regulation of antiapoptotic genes positively controlled by the transcriptional regulator nuclear factor kappaB (NF-kappaB). Consistent with this finding, L. pneumophila triggered nuclear localization of NF-kappaB in human and mouse macrophages in a Dot/Icm-dependent manner. The mechanism of activation at low-dose infections involved a signaling pathway that occurred independently of the Toll-like receptor adaptor MyD88 and the cytoplasmic sensor Nod1. In contrast, high multiplicity of infection conditions caused a host cell response that masked the unique Dot/Icm-dependent activation of NF-kappaB. Inhibition of NF-kappaB translocation into the nucleus resulted in premature host cell death and termination of bacterial replication. In the absence of one antiapoptotic protein, plasminogen activator inhibitor-2, host cell death increased in response to L. pneumophila infection, indicating that induction of antiapoptotic genes is critical for host cell survival.
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Vicki P
authors.initials: VP
authors.lastname: Losick
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Isberg
mesh_terms: D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D020869:Gene Expression Profiling; D006801:Humans; D016952:Legionella pneumophila / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology*; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D053474:Nod1 Signaling Adaptor Protein; D020411:Oligonucleotide Array Sequence Analysis; D017396:Plasminogen Activator Inhibitor 2 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001426:Bacterial Proteins; C501057:DotL protein, Legionella pneumophila; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D017396:Plasminogen Activator Inhibitor 2; D011993:Recombinant Fusion Proteins; D051996:Transcription Factor RelA