Campylobacter jejuni continues to be a leading cause of bacterial enteritis in humans. However, because there are no readily available animal models to study the pathogenesis of C. jejuni-related diseases, the significance of potential virulence factors, such as cytolethal distending toxin (CDT), in vivo are poorly understood. Mice deficient in NF-B subunits (p50 ؊/؊ p65 ؉/؊ ) in a C57BL/129 background are particularly susceptible to colitis induced by another enterohepatic microaerobe, Helicobacter hepaticus, which, like C. jejuni, produces CDT. Wild-type C. jejuni 81-176 and an isogenic mutant lacking CDT activity (cdtB mutant) were inoculated into NF-B-deficient (3X) and C57BL/129 mice. Wild-type C. jejuni colonized 29 and 50% of the C57BL/129 mice at 2 and 4 months postinfection (p.i.), respectively, whereas the C. jejuni cdtB mutant colonized 50% of the C57BL/129 mice at 2 p.i. but none of the mice at 4 months p.i. Although the C57BL/129 mice developed mild gastritis and typhlocolitis, they had robust immunoglobulin G (IgG) and Th1-promoted IgG2a humoral responses to both the wild-type strain and the C. jejuni cdtB mutant. In contrast, 75 to 100% of the 3X mice were colonized with both the wild type and the C. jejuni cdtB mutant at similar levels at all times examined. Wild-type C. jejuni caused moderately severe gastritis and proximal duodenitis in 3X mice that were more severe than the gastrointestinal lesions caused by the C. jejuni cdtB mutant. Persistent colonization of NF-B-deficient mice with the wild type and the C. jejuni cdtB mutant was associated with significantly impaired IgG and IgG2a humoral responses (P < 0.001), which is consistent with an innate or adaptive immune system defect(s). These results suggest that the mechanism of clearance of C. jejuni is NF-B dependent and that CDT may have proinflammatory activity in vivo, as well as a potential role in the ability of C. jejuni to escape immune surveillance. NF-B-deficient mice should be a useful model to further study the role of CDT and other aspects of C. jejuni pathogenesis.Because of the importance of Campylobacter jejuni as a primary enteric pathogen in humans, mice have been used in numerous in vivo experiments involving C. jejuni. However, with few exceptions, oral dosing of different strains of mice with a variety of C. jejuni strains has resulted in intestinal colonization and in some cases bacteremia, but there has been a lack of consistent development of gastroenteritis in the models to date (42).NF-B is a family of proteins that form homo-or heterodimer complexes that regulate transcription of proinflammatory genes (6). These NF-kB complexes are members of the Rel protein family, which includes p50, p65, cRel, Relb, and p52. Several mouse models lacking NF-B family members have been developed. Mice lacking p65 subunits die during embryogenesis, whereas mice homozygously deficient for p50 (p50 Ϫ/Ϫ ) and also heterozygous for p65 (p50 Ϫ/Ϫ p65 ϩ/Ϫ ), referred to as 3X mice, are viable. Both p50 Ϫ/Ϫ and p50 Ϫ/Ϫ p65 ϩ/Ϫ mice developed...
. The infected captive cetaceans were either subclinical, or clinical signs included intermittent regurgitation, inappetance, weight loss, and lethargy. Ulcers were observed in the esophagus and forestomach during endoscopic examination in two of the three captive animals. In the third animal, esophageal linear erosions were visualized endoscopically, and histopathological evaluation of the main stomach revealed multifocal lymphoplasmacytic gastritis with silver-stained spiral-shaped bacteria. Helicobacter cetorum is a fusiform gram-negative bacterium with a single bipolar flagellum. The isolates grow under microaerobic conditions at 37 and 42°C but not at 25°C. H. cetorum is urease, catalase, and oxidase positive, and it is sensitive to cephalothin. The isolates from the wild, stranded dolphins were sensitive to nalidixic acid, whereas the isolates from the collection animals were resistant. By 16S rRNA sequencing it was determined that H. cetorum represented a distinct taxon that clusters most closely with H. pylori. Further studies are necessary to determine the role of H. cetorum in the development of gastric ulcers and gastritis of cetaceans. This is the first description and formal naming of a novel Helicobacter species from a marine mammal. More than 24Helicobacter species have been identified and named in a wide variety of animals, as well as in humans (13,39). Members of the genus Helicobacter are microaerobic, have a fusiform or curved to spiral rod morphology, and are motile by flagella that vary in number and location among different species (13,20,21,26,39,40). Helicobacters colonize the gastrointestinal tract of humans and animals and are known to cause gastrointestinal disease in various hosts, whereas others appear to be nonpathogenic (13,20,30). In humans, Helicobacter pylori is a significant cause of peptic ulcer disease, gastritis, and gastric tumors (25,39,40). In animals, Helicobacter spp. may cause ulcerative or nonulcerative gastritis, typhlocolitis, and hepatitis and can lead to tumors in chronic infections (13,14,17). The ability of gastric Helicobacter spp. to colonize the stomach is largely dependent on the production of urease (4). Urease hydrolyzes urea into ammonia, resulting in alkalinization of the gastric mucosa, which promotes bacterial colonization and survival (4).Gastric ulcers have been reported in cetaceans for several decades (8,33,37,38). Parasitic infections have been associated with some lesions, but in other cases no clearly defined etiologies have been identified. We previously described a novel urease-positive Helicobacter sp. cultured from the main stomachs of stranded Atlantic white-sided dolphins that died on the beach in Cape Cod, Mass., and a beluga whale from Mystic Aquarium, Conn. (23,24). Since then, additional strains of this species were cultured from the feces of a Pacific whitesided dolphin, and an Atlantic bottlenose dolphin from various aquaria in the United States (23). Based on morphological, biochemical, and growth characteristics, as well as 16S rRN...
A 70-kb genomic island (HHGI1) in Helicobacter hepaticus strain ATCC 51449 is a putative pathogenicity island (PAI). To determine the in vivo relevance of this PAI, we inoculated A/JCr mice with one of three strains of H. hepaticus: type strain Hh3B1, which contains the complete PAI, and strains HhNET and HhG, which lack all or large parts of HHGI1, respectively. Mice infected with HhG and HhNET developed less-severe hepatitis than male A/JCr mice infected with Hh3B1.
Helicobacter hepaticus causes hepatitis in susceptible strains of mice. Previous studies indicated that A/JCr mice are susceptible and C57BL/6NCr mice are resistant to H. hepaticus-induced hepatitis. We used F1 hybrid mice derived from A/J and C57BL/6 matings to investigate their phenotype and determine their hepatic gene expression profile in response to H. hepaticus infection. F1 hybrid mice, as well as parental A/J and C57BL/6 mice, were divided equally into control and H. hepaticus-infected groups and euthanized at 18 months postinoculation. Hepatic lesions were evaluated histologically and the differential hepatic gene expression in F1 mice was determined by microarray-based global gene expression profiling analysis. H. hepaticus-infected parental strains including A/J and C57BL/6 mice, as well as F1 mice, developed significant hepatitis. Overall, hepatocellular carcinomas or dysplastic liver lesions were observed in 69% of H. hepaticus-infected F1 male mice and H. hepaticus was isolated from hepatic tissues of all F1 mice with liver tumors. Liver tumors, characterized by hepatic steatosis, developed in livers with high hepatitis scores. To identify gene expression specific to H. hepaticus-induced hepatitis and progression to hepatocellular carcinoma in F1 mice, a method using comparative group transcriptome analysis was utilized. The canonical pathway most significantly enriched was immunological disease. Fatty acid synthase and steaoryl-coenzyme A desaturase, the two rate-limiting enzymes in lipogenesis, were upregulated in neoplastic relative to dysplastic livers. This study suggests a synergistic interaction between hepatic steatosis and infectious hepatitis leading to hepatocellular carcinoma. The use of AB6F1 and B6AF1 mice, as well as genetically engineered mice, on a C57BL/6 background will allow studies investigating the role of chronic microbial hepatitis and steatohepatitis in the pathogenesis of liver cancer.
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