Salmonella effector AvrA regulation of colonic epithelial cell inflammation by deubiquitination.

Department of Pathology, The University of Chicago, Chicago, Illinois, USA.
American Journal Of Pathology (Impact Factor: 4.6). 10/2007; 171(3):882-92. DOI: 10.2353/ajpath.2007.070220
Source: PubMed

ABSTRACT AvrA is a newly described bacterial effector existing in Salmonella. Here, we test the hypothesis that AvrA is a deubiquitinase that removes ubiquitin from two inhibitors of the nuclear factor-kappaB (NF-kappaB) pathway, IkappaBalpha and beta-catenin, thereby inhibiting the inflammatory responses of the host. The role of AvrA was assessed in intestinal epithelial cell models and in mouse models infected with AvrA-deficient and -sufficient Salmonella strains. We also purified AvrA and AvrA mutant proteins and characterized their deubiquitinase activity in a cell-free system. We investigated target gene and inflammatory cytokine expression, as well as effects on epithelial cell proliferation and apoptosis induced by AvrA-deficient and -sufficient bacterial strains in vivo. Our results show that AvrA blocks degradation of IkappaBalpha and beta-catenin in epithelial cells. AvrA deubiquitinates IkappaBalpha, which blocks its degradation and leads to the inhibition of NF-kappaB activation. Target genes of the NF-kappaB pathway, such as interleukin-6, were correspondingly down-regulated during bacterial infection with Salmonella expressing AvrA. AvrA also deubiquitinates and thus blocks degradation of beta-catenin. Target genes of the beta-catenin pathway, such as c-myc and cyclinD1, were correspondingly up-regulated with AvrA expression. Increased beta-catenin further negatively regulates the NF-kappaB pathway. Our findings suggest an important role for AvrA in regulating host inflammatory responses through NF-kappaB and beta-catenin pathways.

1 Bookmark
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The ubiquitin modification has various functions in the host innate immune system in response to the bacterial infection. To counteract the host immunity, Salmonella can specifically target ubiquitin pathways by its effector proteins. In this review, we describe the multiple facets of ubiquitin function during infection with Salmonella enterica Typhimurium and hypothesize how these studies on the host-pathogen interactions can help to understand the general function of the ubiquitination pathway in the host cell.
    Frontiers in Immunology 11/2014; 5:558.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Innate immunity against pathogenic bacteria is critical to protect host cells from invasion and infection as well as to develop an appropriate adaptive immune response. During bacterial infection, different signaling transduction pathways control the expression of a wide range of genes that orchestrate a number of molecular and cellular events to eliminate the invading microorganisms and regulate inflammation. The inflammatory response must be tightly regulated because uncontrolled inflammation may lead to tissue injury. Among the many signaling pathways activated, the canonical Wnt/β-catenin has been recently shown to play an important role in the expression of several inflammatory molecules during bacterial infections. Our main goal in this review is to discuss the mechanism used by several pathogenic bacteria to modulate the inflammatory response through the Wnt/β-catenin signaling pathway. We think that a deep insight into the role of Wnt/β-catenin signaling in the inflammation may open new venues for biotechnological approaches designed to control bacterial infectious diseases.
    Mediators of Inflammation 01/2014; 2014:310183. · 2.42 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The in vitro analysis of bacterial–epithelial interactions in the intestine has been hampered by a lack of suitable intestinal epithelium culture systems. Here, we report a new experimental model using an organoid culture system to study pathophysiology of bacterial–epithelial interactions post Salmonella infection. Using crypt-derived mouse intestinal organoids, we were able to visualize the invasiveness of Salmonella and the morphologic changes of the organoids. Importantly, we reported bacteria-induced disruption of epithelial tight junctions in the infected organoids. In addition, we showed the inflammatory responses through activation of the NF-κB pathway in the organoids. Moreover, our western blot, PCR, and immunofluorescence data demonstrated that stem cell markers (Lgr5 and Bmi1) were significantly decreased by Salmonella infection (determined using GFP-labeled Lgr5 organoids). For the first time, we created a model system that recapitulated a number of observations from in vivo studies of the Salmonella-infected intestine, including bacterial invasion, altered tight junctions, inflammatory responses, and decreased stem cells. We have demonstrated that the Salmonella-infected organoid culture system is a new experimental model suitable for studying host–bacterial interactions.
    Physiological Reports. 09/2014; 2(9).

Full-text (2 Sources)

Available from
Jun 6, 2014