Abstract
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 IFNbeta expression in human lung epithelial cells. We found that factor (IRF)-3 and NF-kappaB-p65 translocated into the nucleus and bound to the IFNbeta 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 IFNbeta 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 IFNbeta 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 IFNbeta in Legionella infection of lung epithelium.
Highlights
The innate immunity serves as a first line defense system against invading pathogens, including bacteria or viruses
IRF3 Is Required for L. pneumophila-stimulated IFN Expression—IFN responses upon Legionella infection led us to assess a possible link between Legionella infection and IRF3 activation
Type I IFNs had been associated with antiviral immune responses, but an increasing body of work demonstrated that type I IFNs played important roles in the host defense against bacterial infections [30]. We expand on this by demonstrating 1) that L. pneumophila induced IFN expression in lung epithelial cells, a process dependent on its type IVB secretion system but not on flagellin; 2) that IPS-1 and IRF3 are crucial for the IFN response to L. pneumophila, and 3) that IPS-1 and IRF3 were important for the control of intracellular replication of L. pneumophila in lung epithelial cells
Summary
The innate immunity serves as a first line defense system against invading pathogens, including bacteria or viruses. IPS-1 Is Required for L. pneumophila-stimulated IFN Expression—IPS-1/MAVS/VISA/Cardif has been demonstrated to be crucial for RIG-I- and MDA5-mediated IRF3 activation and subsequent IFN induction by double-stranded RNA as well as certain viruses and very recently for IFN responses induced by cytosolic B-form DNA via a so far unidentified receptor (10 –13, 27).
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