Legionella pneumophila induces IFNβ in lung epithelial cells via IPS-1 and IRF3, which also control bacterial replication

Legionella pneumophila, a Gram-negative facultative intracellular bacterium, causes severe pneumonia ( Legionnaires' disease). Type I interferons (IFNs) were so far associated with antiviral immunity, but recent studies also indicated a role of these cytokines in immune responses against ( intracellular) bacteria. Here we show that wild-type L. pneumophila and flagellin-deficient Legionella, but not L. pneumophila lacking a functional type IV secretion system Dot/Icm, or heat-inactivated Legionella induced IFN beta expression in human lung epithelial cells. We found that factor (IRF)-3 and NF-kappa B-p65 translocated into the nucleus and bound to the IFN beta gene enhancer after L. pneumophila infection of lung epithelial cells. RNA interference demonstrated that in addition to IRF3, the caspase recruitment domain (CARD)-containing adapter molecule IPS-1 (interferon-beta promoter stimulator 1) is crucial for L. pneumophila-induced IFN beta expression, whereas other CARD-possessing molecules, such as RIG-I ( retinoic acid-inducible protein I), MDA5 ( melanoma differentiation-associated gene 5), Nod27(nucleotide-binding oligomerization domain protein 27), and ASC (apoptosis-associated speck-like protein containing a CARD) seemed not to be involved. Finally, bacterial multiplication assays in small interfering RNA-treated cells indicated that IPS-1, IRF3, and IFN beta were essential for the control of intracellular replication of L. pneumophila in lung epithelial cells. In conclusion, we demonstrated a critical role of IPS-1, IRF3, and IFN beta in Legionella infection of lung epithelium.