The Listeria monocytogenes InlC protein interferes with innate immune responses by targeting the I{kappa}B kinase subunit IKK{alpha}.
Listeria monocytogenes is an intracellular pathogen responsible for severe foodborne infections. It can replicate in both phagocytic and nonphagocytic mammalian cells. The infectious process at the cellular level has been studied extensively, but how the bacterium overcomes early host innate immune responses remains largely unknown. Here we show that InlC, a member of the internalin family, is secreted intracellularly and directly interacts with IKKα, a subunit of the IκB kinase complex critical for the phosphorylation of IκB and activation of NF-κB, the major regulator of innate immune responses. Infection experiments with WT Listeria or the inlC-deletion mutant and transfection of cells with InlC reveal that InlC expression impairs phosphorylation and consequently delays IκB degradation normally induced by TNF-α, a classical NF-κB stimulator. Moreover, infection of RAW 264.7 macrophages by the inlC mutant leads to increased production of proinflammatory cytokines compared with that obtained with the WT. Finally, in a peritonitis mouse model, we show that infection with the inlC mutant induces increased production of chemokines and increased recruitment of neutrophils in the peritoneal cavity compared with infection with WT. Together, these results demonstrate that InlC, by interacting with IKKα, dampens the host innate response induced by Listeria during the infection process.
Gouin
Edith
E
Unité des Interactions Bactéries-Cellules, Département de Biologie Cellulaire et Infection, Institut Pasteur, F-75015 Paris, France.
Adib-Conquy
Minou
M
Balestrino
Damien
D
Nahori
Marie-Anne
MA
Villiers
Véronique
V
Colland
Frédéric
F
Dramsi
Shaynoor
S
Dussurget
Olivier
O
Cossart
Pascale
P
D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology*; D002460:Cell Line; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate; D008089:Listeria monocytogenes / Q000276:immunology / Q000472:pathogenicity; D051379:Mice; D011401:Promoter Regions, Genetic; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020798:Two-Hybrid System Techniques
D001426:Bacterial Proteins; D021122:Protein Subunits; D014409:Tumor Necrosis Factor-alpha; C103178:inlC protein, Listeria monocytogenes; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase