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Cytolethal distending toxin sequence and activity in the enterohepatic pathogen Helicobacter hepaticus.

ABSTRACT: Little is known about the molecular pathogenesis of hepatitis and enterocolitis caused by enterohepatic Helicobacter species. Sonicates of the murine pathogen Helicobacter hepaticus were found to cause progressive cell distension, accumulation of filamentous actin, and G(2)/M cell cycle arrest in HeLa cell monolayers. The genes encoding this cytotoxic activity were cloned from H. hepaticus. Three open reading frames with closest homology to cdtA, cdtB, and cdtC from Campylobacter jejuni were identified. Sonicates of a laboratory strain of Escherichia coli carrying the cloned cdtABC gene cluster from H. hepaticus reproduced the cytotoxic activities seen with sonicates of H. hepaticus. Cytolethal distending toxin activity is a potential virulence determinant of H. hepaticus that may play a role in the pathogenesis of Helicobacter-associated hepatitis and enterocolitis.

SUBMITTER: Young VB

PROVIDER: S-EPMC97119 | biostudies-literature | 2000 Jan

REPOSITORIES: biostudies-literature

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Cytolethal distending toxin sequence and activity in the enterohepatic pathogen Helicobacter hepaticus.

Young V B VB Knox K A KA Schauer D B DB

Infection and immunity 20000101 1

Little is known about the molecular pathogenesis of hepatitis and enterocolitis caused by enterohepatic Helicobacter species. Sonicates of the murine pathogen Helicobacter hepaticus were found to cause progressive cell distension, accumulation of filamentous actin, and G(2)/M cell cycle arrest in HeLa cell monolayers. The genes encoding this cytotoxic activity were cloned from H. hepaticus. Three open reading frames with closest homology to cdtA, cdtB, and cdtC from Campylobacter jejuni were ide ...[more]

PMID: 10603386

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Project description:Helicobacter hepaticus, which induces chronic hepatitis and typhlocolitis in susceptible mouse strains, produces a cytolethal distending toxin (CDT) consisting of CdtA, CdtB, and CdtC. A cdtB-deficient H. hepaticus isogenic mutant (HhcdtBm7) was generated and characterized for colonization parameters in four intestinal regions (jejunum, ileum, cecum, and colon) of outbred Swiss Webster (SW) mice. Inactivation of the cdtB gene abolished the ability of HhcdtBm7 to colonize female mice at both 8 and 16 weeks postinfection (wpi), whereas HhcdtBm7 colonized all of four intestinal regions of three of five males at 8 wpi and then was eliminated by 16 wpi. Wild-type (WT) H. hepaticus was detected in the corresponding intestinal regions of both male and female mice at 8 and 16 wpi; however, colonization levels of WT H. hepaticus in the cecum and colon of male mice were approximately 1,000-fold higher than in females (P < 0.0079) at 16 wpi. Infection with WT H. hepaticus, but not HhcdtBm7, at 8 wpi was associated with significantly increased mRNA level of ileal and cecal gamma interferon (IFN-gamma) in females (P < 0.016 and 0.031 between WT H. hepaticus-infected and sham-dosed females, respectively). In contrast, the mRNA levels of IFN-gamma were significantly higher in the colon (P < 0.0079) and trended to be higher in the cecum (P < 0.15) in the HhcdtBm7-colonized male mice versus the sham-dosed controls at 8 wpi. In addition, mRNA levels of ileal IFN-gamma were significantly higher in the control females than males at 8 wpi (P < 0.016). There were significantly higher Th1-associated immunoglobulin G2a (IgG2a), Th2-associated IgG1 and mucosal IgA (P < 0.002, 0.002, 0.002, respectively) responses in the mice infected with WT H. hepaticus when compared to HhcdtBm7 at 16 wpi. Colonic interleukin-10 (IL-10) expressions at 16 wpi were significantly lower in both female and male mice colonized by WT H. hepaticus or in males transiently colonized through 8 wpi by HhcdtBm7 versus control mice (P < 0.0159). These lines of evidence indicate that (i) H. hepaticus CDT plays a crucial role in the persistent colonization of H. hepaticus in SW mice; (ii) SW female mice are more resistant to H. hepaticus colonization than male mice; (iii) there was persistent colonization of WT H. hepaticus in cecum, colon, and jejunum but only transient colonization of H. hepaticus in the ileum of female mice; (iv) H. hepaticus colonization was associated with down-regulation of colonic IL-10 production.

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Cytolethal distending toxin sequence and activity in the enterohepatic pathogen Helicobacter hepaticus.

Publications

Cytolethal distending toxin sequence and activity in the enterohepatic pathogen Helicobacter hepaticus.

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