ABSTRACT
Yersinia pseudotuberculosis is an enteropathogenic bacteria that disrupts the intestinal barrier and invades its host through gut-associated lymphoid tissue and Peyer's patches (PP). We show that the Y. pseudotuberculosis effector YopJ induces intestinal barrier dysfunction by subverting signaling of the innate immune receptor Nod2, a phenotype that can be reversed by pretreating with the Nod2 ligand muramyl-dipeptide. YopJ, but not the catalytically inactive mutant YopJ(C172A), acetylates critical sites in the activation loops of the RICK and TAK1 kinases, which are central mediators of Nod2 signaling, and decreases the affinity of Nod2 for RICK. Concomitantly, Nod2 interacts with and activates caspase-1, resulting in increased levels of IL-1ß. Finally, IL-1ß within PP plays an essential role in inducing intestinal barrier dysfunction. Thus, YopJ alters intestinal permeability and promotes the dissemination of Yersinia as well as commensal bacteria by exploiting the mucosal inflammatory response.
Subject(s)
Bacterial Proteins/metabolism , Caspase 1/metabolism , Intestines/enzymology , MAP Kinase Kinase Kinases/metabolism , Nod2 Signaling Adaptor Protein/metabolism , Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism , Yersinia pseudotuberculosis Infections/enzymology , Yersinia pseudotuberculosis/metabolism , Animals , Bacterial Proteins/genetics , Caspase 1/genetics , Cell Line , Female , Humans , Intestinal Mucosa/metabolism , Intestines/microbiology , MAP Kinase Kinase Kinases/genetics , Male , Mice , Mice, Inbred C57BL , Nod2 Signaling Adaptor Protein/genetics , Receptor-Interacting Protein Serine-Threonine Kinase 2/genetics , Signal Transduction , Yersinia pseudotuberculosis/genetics , Yersinia pseudotuberculosis Infections/genetics , Yersinia pseudotuberculosis Infections/metabolism , Yersinia pseudotuberculosis Infections/microbiologyABSTRACT
Nucleotide oligomerisation domain 2 (NOD2) is a component of the innate immunity known to be involved in the homeostasis of Peyer patches (PPs) in mice. However, little is known about its role during gut infection in vivo. Yersinia pseudotuberculosis is an enteropathogen causing gastroenteritis, adenolymphitis and septicaemia which is able to invade its host through PPs. We investigated the role of Nod2 during Y. pseudotuberculosis infection. Death was delayed in Nod2 deleted and Crohn's disease associated Nod2 mutated mice orogastrically inoculated with Y. pseudotuberculosis. In PPs, the local immune response was characterized by a higher KC level and a more intense infiltration by neutrophils and macrophages. The apoptotic and bacterial cell counts were decreased. Finally, Nod2 deleted mice had a lower systemic bacterial dissemination and less damage of the haematopoeitic organs. This resistance phenotype was lost in case of intraperitoneal infection. We concluded that Nod2 contributes to the susceptibility to Y. pseudotuberculosis in mice.