The Journal of Experimental Medicine
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Published online 28 August 2006 doi:10.1084/jem.20060766
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 9, 2177-2189
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ARTICLE

 NF-{kappa}B translocation prevents host cell death after low-dose challenge by Legionella pneumophila

Vicki P. Losick2 and Ralph R. Isberg1,2

1 Howard Hughes Medical Institute and 2 Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111

CORRESPONDENCE Ralph R. Isberg: Ralph.Isberg{at}tufts.edu

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 {kappa}B (NF-{kappa}B). Consistent with this finding, L. pneumophila triggered nuclear localization of NF-{kappa}B 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-{kappa}B. Inhibition of NF-{kappa}B 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.

Abbreviations used: CAPE, caffeic acid phenethyl ester; Dot+, WT Legionella pneumophila; hai, h after infection; MAP, mitogen-activated protein; MOI, multiplicity of infection; PAI-2, plasminogen activator inhibitor–2; qPCR, quantitative real-time PCR; TLR, Toll-like receptor.


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