Modulation of host immune responses by the cytolethal distending toxin of Helicobacter hepaticus.
ABSTRACT Persistent murine infection with Helicobacter hepaticus leads to chronic gastrointestinal inflammation and neoplasia in susceptible strains. To determine the role of the virulence factor cytolethal distending toxin (CDT) in the pathogenesis of this organism, interleukin-10-deficient (IL-10-/-) mice were experimentally infected with wild-type H. hepaticus and a CDT-deficient isogenic mutant. Both wild-type H. hepaticus and the CDT-deficient mutant successfully colonized IL-10-/- mice, and they reached similar tissue levels by 6 weeks after infection. Only animals infected with wild-type type H. hepaticus developed significant typhlocolitis. However, by 4 months after infection, the CDT-deficient mutant was no longer detectable in IL-10-/- mice, whereas wild-type H. hepaticus persisted for the 8-month duration of the experiment. Animals infected with wild-type H. hepaticus exhibited severe typhlocolitis at 8 months after infection, while animals originally challenged with the CDT-deficient mutant had minimal cecal inflammation at this time point. In follow-up experiments, animals that cleared infection with the CDT-deficient mutant were protected from rechallenge with either mutant or wild-type H. hepaticus. Animals infected with wild-type H. hepaticus developed serum immunoglobulin G1 (IgG1) and IgG2c responses against H. hepaticus, while animals challenged with the CDT-deficient mutant developed significantly lower IgG2c responses and failed to mount IgG1 responses against H. hepaticus. These results suggest that CDT plays a key immunomodulatory role that allows persistence of H. hepaticus and that in IL-10-/- mice this alteration of the host immune response results in the development of colitis.
Full-textDOI: · Available from: Vincent Young, Mar 25, 2014
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ABSTRACT: Cytolethal distending toxin (CDT) is a heterotrimeric AB-type genotoxin produced by several clinically important Gram-negative mucocutaneous bacterial pathogens. Irrespective of the bacterial species of origin, CDT causes characteristic and irreversible cell cycle arrest and apoptosis in a broad range of cultured mammalian cell lineages. The active subunit CdtB has structural homology with the phosphodiesterase family of enzymes including mammalian DNase I, and alone is necessary and sufficient to account for cellular toxicity. Indeed, mammalian cells treated with CDT initiate a DNA damage response similar to that elicited by ionizing radiation-induced DNA double strand breaks resulting in cell cycle arrest and apoptosis. The mechanism of CDT-induced apoptosis remains incompletely understood, but appears to involve both p53-dependent and -independent pathways. While epithelial, endothelial and fibroblast cell lines respond to CDT by undergoing arrest of cell cycle progression resulting in nuclear and cytoplasmic distension that precedes apoptotic cell death, cells of haematopoietic origin display rapid apoptosis following a brief period of cell cycle arrest. In this review, the ecology of pathogens producing CDT, the molecular biology of bacterial CDT and the molecular mechanisms of CDT-induced cytotoxicity are critically appraised. Understanding the contribution of a broadly conserved bacterial genotoxin that blocks progression of the mammalian cell cycle, ultimately causing cell death, should assist with elucidating disease mechanisms for these important pathogens.Microbiology 05/2011; 157(Pt 7):1851-75. DOI:10.1099/mic.0.049536-0 · 2.84 Impact Factor
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ABSTRACT: Multiple pathogenic Gram-negative bacteria produce cytolethal-distending toxins (CDTs). CDT is typically composed of three subunits: the catalytic subunit CdtB has DNase I-like activity, whereas CdtA and CdtC are binding proteins for delivering CdtB into target cells. Translocation of CdtB to the nucleus induces genotoxic effects on host DNA, triggering DNA repair cascades that lead to cell cycle arrest and eventual cell death. Several lines of evidence indicate that this toxin contributes to the pathogenicity of CDT-producing bacteria in vivo. Helicobacter hepaticus and Campylobacter jejuni CDTs are essential for persistent infection of the gastrointestinal tract and increase the severity of mucosal inflammation or liver disease in susceptible mouse strains. Haemophilus ducreyi CDT may contribute to the pathogenesis of chancroid in rabbits. Recently, H. hepaticus CDT has been shown to play a crucial role in promoting the progression of infectious hepatitis to pre-malignant, dysplastic lesions via activation of a pro-inflammatory NF-kappaB pathway and increased proliferation of hepatocytes, providing the first evidence that CDT has carcinogenic potential in vivo. Thus, both in vitro and in vivo data indicate that CDT is a bacterial virulence factor.Cellular Microbiology 07/2008; 10(8):1599-607. DOI:10.1111/j.1462-5822.2008.01173.x · 4.82 Impact Factor
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ABSTRACT: Helicobacter hepaticus colonizes the murine intestine and has been associated with hepatic inflammation and neoplasia in susceptible mouse strains. In this study, the catalase of an enterohepatic Helicobacter was characterized for the first time. H. hepaticus catalase is a highly conserved enzyme that may be important for bacterial survival in the mammalian intestine. Recombinant H. hepaticus catalase was expressed in Escherichia coli in order to verify its enzymic activity in vitro. H. hepaticus catalase comprises 478 amino acids with a highly conserved haem-ligand domain. Three conserved motifs (R-F-Y-D, RERIPER and VVHAKG) in the haem-ligand domain and three surface-predicted motifs were identified in H. hepaticus catalase and are shared among bacterial and mammalian catalases. H. hepaticus catalase is present in the cytoplasmic and periplasmic compartments. Mice infected with H. hepaticus demonstrated immune responses to murine and H. hepaticus catalase, suggesting that Helicobacter catalase contains conserved structural motifs and may contribute to autoimmune responses. Antibodies to H. hepaticus catalase recognized murine hepatocyte catalase in hepatic tissue from infected mice. Antibodies from sera of H. hepaticus-infected mice reacted with peptides comprising two conserved surface-predicted motifs in H. hepaticus catalase. Catalases are highly conserved enzymes in bacteria and mammals that may contribute to autoimmune responses in animals infected with catalase-producing pathogens.Microbiology 05/2007; 153(Pt 4):1006-16. DOI:10.1099/mic.0.29184-0 · 2.84 Impact Factor