In Vivo Modeling of Helicobacter-associated Gastrointestinal Diseases

Richard L. Ferrero; James G. Fox

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Mobley HLT, Mendz GL, Hazell SL, editors. Helicobacter pylori: Physiology and Genetics. Washington (DC): ASM Press; 2001.

Helicobacter pylori: Physiology and Genetics.

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Chapter 45In Vivo Modeling of Helicobacter-associated Gastrointestinal Diseases

Richard L. Ferrero and James G. Fox.

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Spiral- and helical-shaped microorganisms were first observed in the gastric mucosae of animals over a century ago, yet the inability of workers to culture the organisms in vitro precluded further studies on the roles of these bacteria in the pathogenesis of disease (8, 157). The development of new bacteriological methods in the 1970s and 1980s permitted the isolation from the intestinal mucosae and reproductive tracts of animals of a novel family of curved-shaped, gram-negative bacteria with fastidious growth requirements. These bacteria, which belonged to a new genus Campylobacter, were subsequently identified as important causes of gastrointestinal and reproductive disease in human and nonhuman animal hosts. In 1983, Marshall and Warren reported that a "campylobacter-like organism" was responsible for gastritis and peptic ulcer disease in humans (118). Subsequent studies revealed that this organism differed from Campylobacter spp. in several important taxonomic respects (83, 152). A new genus, Helicobacter, was created, and the name Helicobacter pylori sp. nov. was assigned to this gastric pathogen (83).

The Helicobacter genus currently comprises over 20 bacterial species, each of which colonizes either the gastric or intestinal mucosa of mammalian hosts (for a review see reference 69). Helicobacter spp. generally possess a spiral- or helical-shaped morphology, are motile, and require microaerobic culture conditions for optimum growth. While several gastric Helicobacter spp. such as H. pylori and the ferret Helicobacter sp., Helicobacter mustelae, naturally infect a highly restricted number of animal hosts, others exhibit a much broader host specificity (107). Examples of the latter are Helicobacter felis, Helicobacter heilmannii, and related bacteria, which naturally colonize cats, dogs, and humans (22, 33, 87, 91, 133, 135, 182).

The presence of Helicobacter spp. in the gastric mucosa is associated with inflammation and/or ulceration, and these bacteria are recognized as important pathogens in gastroduodenal disease. There is now mounting evidence that suggests that enterohepatic Helicobacter spp. may also be pathogenic for the host (69). Indeed, enterohepatic helicobacters have been linked to severe inflammatory lesions in the lower bowel, gallbladders, and livers of infected mammalian hosts, including humans (4, 13, 47, 56, 58, 60, 64, 65, 66, 72, 75, 92, 168). Several natural and experimental animal models of helicobacter infection are currently available and should allow further investigations into the pathogenetic mechanisms involved in gastric and enterohepatic diseases due to these bacteria.

Helicobacter Colonization of Animal Hosts

Gastric Helicobacter spp

Natural infections

The seminal work of Salomon and Bizzozeroni in the 1890s described the presence of spiral- and helical-shaped bacteria in the gastric mucosae of humans, cats, and dogs (8, 157). Although similar observations of gastric bacteria were made throughout most of the last century (26, 79, 169), the role of these organisms in disease remained a contentious issue until well after the discovery of H. pylori in 1983 by Marshall and Warren (118).

Various other gastric Helicobacter spp. have now been isolated and characterized (Table 1). The first of these was H. mustelae, a natural colonizer of the gastric mucosa of ferrets (67), followed by H. felis, which naturally colonizes the stomachs of both cats and dogs (109, 145). Other types of gastric Helicobacter-like organisms (GHLO) (also known as Gastrospirillum species) were found to colonize the gastric mucosa of domestic carnivores, swine, and nonhuman primates in high numbers (1, 22, 31, 86, 90, 94, 106, 129, 151, 166). Though few of these organisms have been successfully cultured in vitro (1, 86), the sequencing of PCR-amplified DNA from the gastric biopsies of infected animals has shown these bacteria to be phylogenetically related to the human GHLO, "H. heilmannii" (135, 166).

Table 1

The principal pathogenic Helicobacter spp., their hosts, and the diseases caused^a.

In addition to harboring "H. heilmannii"-like bacteria, nonhuman primates are commonly infected with Helicobacter spp. that have a very high degree of similarity to H. pylori. Indeed, in rhesus and cynomolgus monkeys, these gastric Helicobacter spp. are indistinguishable from H. pylori (28, 31), whereas pig-tailed macaques are colonized by Helicobacter nemestrinae (12). From recent 16S rRNA analysis of the sole strain of H. nemestrinae available from the American Type Culture Collection, it appears that this isolate is also indistinguishable from H. pylori (23). Cheetahs and one colony of domestic cats have been found to naturally harbor Helicobacter acinonychis (35) and H. pylori (45, 73), respectively.

Experimental infections

Initial attempts to establish H. pylori infection models in laboratory animals such as mice, rats, and rabbits were unsuccessful (14). Although immunodeficient mice could be temporarily colonized by H. pylori bacteria, such models had restricted applications (99). Alternative Helicobacter models were thus developed using animals that were either already naturally infected with closely related Helicobacter spp., such as ferrets (61) and nonhuman primates (31), or with those that could be experimentally infected with H. pylori, including gnotobotic piglets (103) and dogs (149) (Table 1). It was subsequently shown that rodents were susceptible to infection with H. felis (Fig. 1) (108), thus paving the way for affordable animal model studies that did not require specialized facilities or expertise.

Figure 1

Experimental gastric helicobacter infections in mice. Panels A and B show gastric tissue sections from mice infected with the H. pylori SS1 strain (arrows). Large numbers of bacteria are seen colonizing the lumen of the gastric glands (Warthin-Starry (more...)

The first report of experimental H. pylori infections in immunocompetent mice was published in 1995 (117). Using fresh clinical H. pylori isolates that had not been cultured extensively in vitro, the authors were able to establish a transient infection in the animals. Two years later, an H. pylori mouse model permitting the establishment of long-term, high bacterial density H. pylori colonization was described (Fig. 1) (111). Experimental H. pylori infections have also been developed in Mongolian gerbils (119, 189) and guinea pigs (163), cats (58a), and macaque monkeys (29, 30).

Enterohepatic Helicobacter spp

An increasing number of Helicobacter spp. have been isolated from the intestinal tracts of rodents, birds, cats, dogs, and primates (Table 1) (65, 66, 75, 76, 112, 122, 160, 162, 167, 168, 180). Several of these intestinal Helicobacter spp. appear to be part of the autochthonous microbiota of animal hosts (81, 122, 162), while others have been implicated as etiological agents in diseases involving the gastrointestinal and reproductive tracts of infected hosts (Table 2). Indeed, intestinal Helicobacter spp. have been associated with inflammatory lesions in the lower bowel of immunocompromised humans (47) and mice (13, 58, 68, 78), and with chronic hepatitis (72, 77, 92, 179, 180, 183), hepatocellular carcinoma (92, 180), and cholecystitis (64, 76). Several experimental models have been developed to study the inflammatory processes induced by the murine enterohepatic Helicobacter sp., Helicobacter hepaticus (Fig. 2) (13, 92, 179, 183). Helicobacter spp. have also been associated with spontaneous abortions in sheep and lambs (24). In rare instances, intestinal helicobacters have been isolated from the gastric mucosa of the host, though the potential of these bacteria to induce inflammation in the stomach has not been unequivocally determined (105).

Table 2

Experimental parameters to consider when establishing an H. pylori mouse infection model.

Figure 2

Extragastric Helicobacter spp. and the induction of hepatic inflammatory lesions in mice. (A) A transmission electron micrograph shows the distinctive spiral morphology and bipolar flagella of H. hepaticus. Light micrographs depict (B) H. bilis-like organisms (more...)

Bacterial Host Specificity and Gastric Inflammation

Gastric Helicobacter spp. exhibit different degrees of host specificity, with H. pylori and H. mustelae naturally infecting a very narrow range of animal hosts (Table 1) (107). H. mustelae is particularly selective in its choice of host because infections with this organism have only been described in ferrets (138). High levels of host specificity in gastric helicobacters are most evident in those species that adhere tightly to host tissues (Fig. 3) (138, 139) and are able to agglutinate red blood cells (173).

Figure 3

Bacterium-host cell interactions during gastric helicobacter infection. Transmission electron photomicrographs show (A) H. felis, (B) H. pylori, (C) H. heilmannii, and (D) H. mustelae bacteria (arrows) in the gastric mucosae of experimentally infected (more...)

Electron microscopic studies of H. pylori- and H. mustelae-infected tissues have shown the presence of adherence pedestal-like protrusions of host cell membranes at the site of bacterium-host cell contact (111, 137, 139, 154). Moreover, the adherence of H. pylori bacteria with AGS cells in vitro has been associated with cytoskeletal rearrangements in the cells (159). It was suggested that close interactions of H. pylori and H. mustelae bacteria with the gastric epithelium of humans and ferrets, respectively, might per se be a requisite event for ulcerogenesis in these hosts (138). H. pylori bacteria were shown to interact intimately with the gastric mucosa of experimentally infected mice (Fig. 3) (111) and gnotobiotic pigs (102); however, the former did not develop ulcers while the latter did. Moreover, an "H. heilmannii"-like bacterium in swine induced gastric ulcers in the pars esophaga of infected animals despite the absence of tissue adherence by the organism (22). While there are obvious differences between swine and human peptic ulcer disease, similar histopathological changes associated with ulceration, including the presence of Helicobacter-induced antral gastritis, have been observed in both diseases (22).

Experiments in transgenic mice expressing human Lewis^b blood group antigen, a receptor for the H. pylori adhesin known as BabA2, showed that a more intimate interaction of H. pylori bacteria with host tissues favored the formation of severe inflammatory lesions such as atrophic gastritis in this model (85). This finding is consistent with those from clinical studies that reported that the presence of a babA2 genotype in H. pylori strains was significantly associated with duodenal ulcer and adenocarcinoma formation in the host (82). Nevertheless, the ability of the apparently nonadherent Helicobacter spp. H. felis and H. heilmannii to induce strong inflammatory responses in infected hosts suggests that close tissue interactions are not a sine qua non for Helicobacter-induced inflammation (35, 42, 49, 70, 107, 110, 129, 130, 155).

Factors Mediating Helicobacter-induced Inflammation and Tissue Damage

Bacterial Factors

LPS

In most gram-negative bacteria, lipopolysaccharide (LPS), or endotoxin, plays a key role in the induction of host immune responses via CD14-mediated signaling through Toll-like receptor 4 structures present on the surfaces of leukocytes (175). Studies on the role of Helicobacter LPS in inflammation demonstrated that C3H/HeJ mice, which exhibit a defective response to LPS due to a mutation in the Toll-like receptor 4 gene (147, 148), developed a very mild gastritis in response to H. felis infection (156). In contrast, congenic LPS-responder C3H/He mice displayed severe gastric atrophy, suggesting the modulation of host gastritis via an LPS-dependent release of inflammatory cytokines by activated macrophages (156).

While H. felis LPS appears to exert a proinflammatory effect on host cells, H. pylori endotoxin possesses a very low biological activity (132) and was a poor inducer of cytokine production by inflammatory cells in vitro (11). H. pylori (3) and H. mustelae (127, 136) LPS possess epitopes with similarity to human blood group antigens, and it was suggested that such structures may be involved in a form of molecular mimicry, implicated in the formation of gastric atrophy in the host (3, 136). However, the findings from different studies have been contradictory, and it is now unclear whether H. pylori LPS does indeed play such a role (150, 184, 185). It is more likely that the low immunostimulatory activity of H. pylori LPS represents an adaptation of the bacterium to the host that allows it to establish a chronic infection. Taken together, it appears that H. pylori LPS is unlikely to be a major promoter of gastric inflammation in the host.

The "Cag" pathogenicity island

Several bacterial factors have been identified as being potential mediators of Helicobacter-induced inflammation. The best characterized of these factors are encoded by a 40-kb pathogenicity island (PAI) termed Cag, after the cytotoxin-associated gene (cagA) found within the island, which consists of approximately 30 open reading frames (15). A functional Cag PAI is required for the internalization (and tyrosine phosphorylation) of CagA within gastric epithelial cells, and it has therefore been proposed that the Cag PAI is involved in the delivery of effector molecules into host cells (5, 137, 170). In addition, several other Cag PAI-related proteins are required for the activation in gastric epithelial cells of the transcription factor nuclear factor -κB (NF-κB), which plays a key role in host immune responses and inflammation (100, 131, 161). The up-regulated expression of NF-κB-dependent genes, such as those encoding the proinflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-α), is likely to contribute to the recruitment and activation of neutrophils and mononuclear cells observed during H. pylori-induced inflammation. Consistent with this, infections with CagA⁺H. pylori strains were associated with increased levels of interleukin-1β (IL-1β) and IL-8 in the gastric mucosa (20, 146, 187), together with more severe neutrophil and mononuclear cell infiltrates, particularly in the antrum (146, 187).

Although animal hosts infected with non-H. pylori helicobacters develop severe chronic gastritis (Fig. 1), scientists have been unable to provide definitive evidence for the presence of Cag PAI equivalents in these bacteria (48, 125). The induction of chronic gastritis in Helicobacter-infected animal hosts may therefore be independent of the effects mediated by the Cag PAI. Also, the infrequent occurrence of neutrophils as a cellular component of Helicobacter-induced inflammation in mice (35, 52, 70, 125, 155) can at least be partly accounted for by the absence in this host of a homolog of human IL-8. Nevertheless, germ-free mice with H. felis infection displayed large numbers of neutrophils in their gastric mucosa, suggesting that mice that have been in contact with commensal organisms may be less responsive in this respect (107, 108).

Proinflammatory H. pylori Proteins

Studies have shown that putative surface-associated proteins present in "water extracts" of H. pylori bacteria were able to attract and activate inflammatory cells, including macrophages and neutrophils (40, 115, 116). One of these proteins, urease, was highly effective in inducing macrophages to produce reactive oxygen intermediates and the proinflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α (88). Given that urease is present in all gastric Helicobacter spp. and several nongastric species (for a review, see reference 50), this enzyme is likely to represent an important proinflammatory factor in gastric as well as several enterohepatic Helicobacter spp. infections.

Two additional H. pylori proteins that were recently described as having proinflammatory effects on host cells are the "neutrophil-activating protein" (NAP), which was shown to promote adhesion of neutrophils to endothelial cells and to induce these cells to produce reactive oxygen intermediates (46, 158), and a 34-kDa outer membrane protein (OipA), the presence of which was associated with the induction of significantly greater amounts of IL-8 secretion in gastric cell lines (188).

Cellular Toxins

The H. pylori vacuolating cytotoxin (VacA)

Helicobacter spp. toxins have been implicated in lesion formation associated with gastric and enterohepatic infections. The H. pylori VacA protein was the first of these toxins to be identified and characterized (19, 55, 114). This protein is processed and secreted by H. pylori cells as a 90-kDa polypeptide, and was described as inducing a vacuolating cytotoxic effect on HeLa cells in vitro (19, 55, 114), due to an osmotic imbalance and the accumulation of late endosomal compartments in the cells (126). H. pylori strains that produced toxinogenic forms of VacA were most frequently associated with duodenal ulcer disease (55). In addition, administration to mice of purified VacA or sonicated cell extracts of a toxinogenic H. pylori strain induced ulcer-like lesions in the animals (174). For these reasons, VacA was proposed to mediate ulcer formation in the host. Peptic ulcers have also been observed in gnotobiotic piglets and Mongolian gerbils colonized with H. pylori (93, 103, 119), as well as in ferrets, mice, and swine infected with non-H. pylori Helicobacter spp. (22, 35, 67, 138). At least one of these non-H. pylori species (H. mustelae) does not produce vacuolating cytotoxin activity in vitro (128), suggesting that other factors may also contribute to ulcerogenesis.

Toxinogenic activity in H. pylori is dependent upon the vacA genotype of the strain (6, 113, 141). It was recently shown that VacA molecules exhibit different cell specificities according to the presence of specific receptors on host cells, and this was dependent on the type of allele present in the mid-region of the vacA gene (141). VacA binding specificity to host receptor sites might also explain the absence of epithelial vacuolation or gastritis in piglets administered toxinogenic H. pylori bacteria (32).

Toxins of enterohepatic Helicobacter spp

Various Helicobacter spp. were shown to produce toxins with a granulating activity for a murine liver cell line (172). This activity was independent of vacuole formation in HeLa cells and was greatest in filter-sterilized culture supernatants from H. hepaticus isolates. The factor responsible for this activity had an approximate molecular mass of 100 kDa but was not characterized any further. Recently, another toxin distinct from the hepatotoxic factor described above was identified in H. hepaticus, as well as in several other enterohepatic Helicobacter spp. (17, 190), and shown to cause progressive cell distensions, accumulation of filamentous actin, and G₂/M cell cycle arrest in HeLa cells (191). The genes encoding this cytotoxic activity were cloned and shown to have the highest levels of homology with the cytolethal distending toxin (cdtA, cdtB, and cdtC) genes of Campylobacter jejuni (191). As H. hepaticus induces the proliferation of intestinal and hepatic host cells in vivo, it is unlikely that enterocytes or hepatocytes are the target cells for H. hepaticus cytolethal distending toxin (Cdt). Instead, this toxin may play a role in the pathogenesis of enterohepatic disease by targeting lymphocytes and causing cell cycle arrest. While the mode of action of H. hepaticus Cdt on eukaryotic cells is unknown, it was recently shown that bacterial Cdt-induced cell cycle arrest in Escherichia coli was associated with a DNase activity intrinsic to the CdtB polypeptide (39).

Host Factors

Gastric inflammation

The observation that various animal hosts infected with the same Helicobacter sp. develop different types of inflammatory lesions is strongly suggestive of the importance of host factors in the induction of lesion formation. Moreover, studies in mice have shown important differences in host-dependent inflammation due to gastric Helicobacter infection (125, 155, 156, 171). In the H. felis mouse model, certain inbred strains of mice, such as C57BL/6, C3H/He, and SJL animals, rapidly developed severe atrophic gastritis after infection, whereas BALB/c and CBA mice developed little or no gastritis in the early phase of infection (≤6 months) (125, 155). Similar differences in the levels of gastric inflammation were observed between C57BL/6 and C3H/He mice that had been infected with H. pylori (155, 176). Interestingly, genetic crosses between mice that developed severe Helicobacter-induced inflammation (responders) with those with low levels of gastritis (nonresponders) revealed a dominance of the nonreponsive phenotype (171). It was, however, shown that even low-responder mice, such as BALB/c animals, could develop specific inflammatory lesions if infected for long enough periods (42). Indeed, BALB/c mice with prolonged H. felis infection (>22 months) developed gastric mucosa-associated lymphoid tissue (MALT) reminiscent of H. pylori-induced human MALT lymphoma lesions (42).

The inflammatory lesions induced by chronic Helicobacter infection in mice affect glandular and lymphoid tissues. As the same bacterial strain has been used in many of these studies, the dichotomy in inflammatory lesion types is most likely dependent on host factors. Studies in B- and T-cell-deficient mice showed that the host T-cell response is a critical mediator of H. felis-associated inflammation (153). Given that C57BL/6 mice develop a default T-helper-1 (Th-1) type response to Helicobacter infection while BALB/c animals exhibit a dominant Th-2 phenotype, it is possible that the Th phenotype of the host is a determining factor in lesion formation, with strong Th-1 responses favoring glandular tissue damage (gastric hyperplasia and atrophy), whereas Th-2 responses are linked to B-cell lymphomagenesis (49). Consistent with this, C57BL/6 knockout mice that were unable to produce IL-10, a key cytokine in Th-2-type responses, rapidly developed a severe gastric hyperplasia following H. felis infection (7). In addition, it was shown that H. felis-infected C57BL/6 mice with a concurrent helminth infection had significantly less Helicobacter-induced gastric atrophy and mucous cell hyperplasia despite the presence of chronic inflammation (59). This effect was associated with a shift in the host's immune response toward a dominant Th-2 phenotype due to the presence of the parasite (59).

Hepatic inflammation

Host-dependent factors in hepatic lesion formation in response to H. hepaticus infection have also been documented. Chronic active hepatitis was found to be associated with enzootically infected colonies of a variety of mouse strains, including A/JCr, BALB/cAnNCr, SJL/NCr, SCID/NCr, and C3H/HeNCr (65, 180). In contrast, other mice (C57BL/6) from the same institution were reported to be resistant to liver disease. To demonstrate the causal role of H. hepaticus in murine hepatitis, liver suspensions from affected mice and cultures of the bacterium were injected intraperitoneally into naive animals (65, 180). Advanced liver lesions in infected susceptible mice were characterized by the presence of hepatocytomegaly, extensive bile ductular hyperplasia, and large peribiliary lymphoid nodules with cholangitis (72, 179, 180). Moreover, male AJCr mice (>1 year of age) developed preneoplastic hepatocellular foci and hepatocellular tumors (179, 180). The identity of host genetic and environmental factors involved in H. hepaticus-induced hepatic disease have begun to be elucidated; for example, using AXB recombinant inbred mice, it has been shown that hepatic disease due to H. hepaticus has a multigenic basis (92). Several investigators have also presented data supporting a role for H. hepaticus in promoting hepatic tumorigenesis (72, 179, 180).

Carcinogenesis

Gastric Carcinoma

Adenocarcinoma

There is overwhelming evidence for the carcinogenic potential of H. pylori in humans. It was first shown by epidemiological studies that the presence of chronic H. pylori infection increased the relative risk for gastric adenocarcinoma formation in humans (134, 144). H. pylori was subsequently identified as the etiological agent of chronic atrophic gastritis, a prerequisite event in the currently accepted model of gastric cancerogenesis proposed by Correa (18), in which chronic atrophic gastritis progresses to atrophy, intestinal metaplasia, and dysplasia. A mechanistic basis for the link between H. pylori infection and gastric cancerogenesis was recently provided by studies on individuals from families with a history of gastric cancer. It was shown that polymorphisms in the gene cluster encoding IL-1β, an important proinflammatory cytokine and a powerful inhibitor of gastric acid, were linked to increased IL-1β secretion, hypochlorhydria, and an increased risk of gastric cancer in the host (38).

Numerous models of gastric cancer involving chemical carcinogens have been described; however, in the interests of brevity, this review will focus only on those models in which Helicobacter served as the carcinogenic factor.

Mice

Helicobacter infection in C57BL/6 mice has been shown to reproduce many of the histologic changes associated with the early stages of gastric neoplasia in humans. Infection of C57BL/6 mice with either H. pylori or H. felis induced severe hyperplasia of the gastric mucosa and atrophy of the chief and parietal cells (125, 153, 155, 171). In mice with chronic H. felis infection (6 to 12 months postinfection), increases in the apoptotic rate of gastric epithelial cells resulted in the loss of parietal and chief cells from the fundic glands (71, 178). This increased rate of apoptosis was followed by increased levels of cell proliferation, as determined by the amounts of proliferating cell nuclear antigen staining, and 5-bromo-2′-deoxyuridine incorporation in gastric tissues from infected mice (71). Aberrant mucosal cell proliferation in H. felis-infected mice resulted in the development of intestinal metaplasia, characterized by the presence of Alcian blue staining (at pH 2.5 and 1.0), and glandular dysplasia. Despite the significant changes observed in the mice, none developed advanced lesions consistent with gastric neoplasia, even after relatively long periods of chronic infection (1 year). Interestingly, accelerated gastric carcinogenesis was observed in transgenic INS-GAS mice with chronic hypergastrinemia and concurrent H. felis infection (177).

The Mongolian gerbil

In the Mongolian gerbil model, long-term experimental H. pylori infection was shown to induce gastric carcinogenesis (181). After a short period of colonization, the animals developed active chronic gastritis, intestinal metaplasia, and gastric ulcer (93, 181). Metaplastic glands situated in the pyloric region of the stomach were composed of columnar cells containing little or no mucus and moderate numbers of goblet cells producing si-alomucins and occasionally sulfomucins (93). At 62 weeks postinfection, 37% (10 of 27) of the infected animals developed well-differentiated intestinal-type epithelium, which was histologically similar to that of adenocarcinoma in humans (181). Such tumors were invasive and were associated with areas of metaplastic epithelium, suggestive of a similar carcinogenic process to that in humans.

Host and environmental factors

Gastric cancer is a very rare event in H. pylori-infected humans, with less than 1% of individuals estimated to develop gastric neoplasia as a result of the infection (142). Although some countries with very high prevalence rates for H. pylori have a comparably high incidence of gastric cancer, this relationship does not hold for all countries. An explanation for this enigma recently arose from work in the H. felis mouse model, which showed that a concurrent parasitic infection could attenuate Helicobacter-induced gastric atrophy formation, and thus reduce the risk of gastric carcinogenesis (59).

In common with other neoplasias, gastric carcinogenesis is likely to be a multifactorial process, which is dependent on the presence of both chronic helicobacter infection and certain host and/or environmental factors. The influence of host genetic determinants on chronic H. felis infection was investigated in mice affected in tumor suppressor genes apc (adenomatous polyposis coli) (63) and p53 (71) that had been back-crossed into a C57BL/6 background. Not only did the apc mutation not lead to an accelerated rate of gastric neoplasia in H. felis-infected mice when compared to wild-type infected C57BL/6 animals, but these mutant mice actually exhibited less severe inflammatory responses, suggesting that this tumor suppressor gene may have a novel role in host immune responses to gastric Helicobacter infection (63). In contrast, mice with a targeted disruption of one p53 allele exhibited a higher proliferative index than infected wild-type mice at 1 year postinfection (71). While the p53 knockout animals did not develop frank neoplasia, the loss of this suppressor gene may increase the risk of gastric cancer in the host.

High levels of salt consumption are associated with an elevated risk of gastric carcinoma in humans (62). Studies in rats demonstrated that salt had a cancer-promoting effect when administered to animals in combination with the carcinogen N-methyl-N′-nitro-N-nitrosoguanidine. To investigate the potential co-carcinogenic effect of salt during chronic gastric helicobacter infection, C57BL/6 mice that had been infected with H. pylori SS1 were fed a high-salt diet, and the development of gastric lesions in these mice was compared to that in animals that had either been infected with H. pylori or given the high-salt diet alone (62). The major findings of this study were that excessive salt intake enhanced the degree of H. pylori colonization in the animals and led to increased cell proliferation in the proximal corpus and antrum and a reduction in parietal cell numbers, resembling glandular atrophy. Thus, it was shown for the first time that dietary salt may act as a cofactor in gastric carcinogenesis associated with chronic H. pylori infection.

MALT lymphoma

Epidemiological studies have shown that H. pylori infection is a risk factor for B-cell MALT lymphoma formation in humans (142, 143). A causal link between H. pylori infection and low-grade MALT lymphoma was provided by treatment studies in which individuals in whom the infection had been eradicated by antimicrobial treatment also displayed regression of the lymphoma lesions (186). Furthermore, long-term Helicobacter infection in ferrets (43) and mice (41, 42) induced in these animal hosts the formation of MALT lesions with similarities to human low-grade B-cell lymphomas of the stomach. There is evidence to suggest that chronic Helicobacter infection provides the antigenic stimulus for low-grade MALT lymphoma formation, whereas the maintenance and progression of tumors to a high-grade state depend on deregulated immune responses involving perhaps autoreactive T cells (41, 84).

H. felis infection of BALB/c mice represents a model of human gastric MALT lymphoma formation (41, 42). It was reported that from 22 months postinfection, a proportion of BALB/c mice with H. felis infection (38%) developed MALT lymphoma lesions with histological features reminiscent of the human disease (42). In addition, antimicrobial therapy of long-term H. felis-infected mice (20 months) resulted in both the eradication of the infection and a reduction in the proportion of animals with MALT lymphoma compared to mice not given antibiotics (23% versus 75%, respectively) (41). Antibiotic-treated mice also displayed lower proportions of intermediate- and high-grade B-cell lymphomas than untreated animals (6 to 39% and 0 to 6%, respectively). This work showed that eradication of the infection caused regression of low-grade tumors and the inhibition of B-cell gastric MALT lymphoma progression toward high-grade lesions.

Hepatocellular carcinoma

The A/JCr inbred mouse strain at the animal research facility of the National Cancer Institute in Maryland was unexpectedly noted to have a high incidence of active chronic hepatitis and hepatocellular cancer (72, 180). Histological studies of the tissues from the animals, together with taxonomic investigations of bacteria recovered from the tissues, led to the discovery of H. hepaticus (72, 180). Liver lesions in H. hepaticus-infected mice were characterized by focal necrosis and mononuclear cell inflammation in the early phases of infection (1 to 4 months) that were followed by more extensive lesions at 6 to 8 months postinfection, including hepatocytomegaly, bile duct hyperplasia, and a peribiliary inflammatory response. An age-related increase in proliferating cell nuclear antigen hepatocyte nuclear labeling index was also observed. Chronic proliferative hepatitis in A/JCr and B6C3F1 mice was associated with an increased risk of hepatocellular carcinoma (72, 92). The parallels between H. hepaticus-induced liver cancer in mice and gastric neoplasia associated with chronic Helicobacter infection in the stomach suggest that similar processes may be involved in the cellular transformations occurring in these otherwise morphologically distinct tissues.

Applications of Helicobacter Infection Models

Antimicrobial Treatment Studies

The need for new antibiotic regimens in the treatment of human H. pylori infection and the lack of correlation between in vitro and in vivo antibiotic efficacy have led to the use of animal models for preclinical evaluations of antibiotic efficacy. It was shown that Helicobacter infections in mice, ferrets, and gnotobiotic piglets all responded favorably to multiple antibiotic treatments frequently used to eradicate H. pylori infections in humans (25, 101, 140). Also, in common with clinical investigations, monotherapies were generally found to have a poor level of efficacy against gastric Helicobacter infection in these animal hosts, thus demonstrating the validity of such models for therapeutic studies and drug assessment. Treatment protocols used against gastric Helicobacter infection have since been shown to be equally effective in eradicating H. hepaticus from certain colonies of mice (57). Recently, studies in H. pylori SS1-infected mice demonstrated that Helicobacter infection models could also be used to address questions relating to the development of antimicrobial resistance in H. pylori in vivo and to the study of the molecular mechanisms involved in resistance (95, 96).

Immunological and Host Response Studies

Despite the obvious differences between human and animal hosts, a great deal has been learned regarding host immune responses to mucosal Helicobacter infection through the use of animal models. Helicobacter-infected rodents, gerbils, ferrets, cats, and monkeys all develop strong humoral responses to the bacteria at both systemic and mucosal sites (31, 52, 54, 73, 74). In common with human H. pylori-associated gastritis, the local inflammatory infiltrates in infected animal hosts are characterized by the presence of large CD3⁺T-lymphocyte populations, the majority of which have a CD4⁺phenotype (36, 45, 49, 73). Moreover, CD4⁺T cells recovered from the splenic and/or gastric tissues of Helicobacter-infected mice display a phenotype consistent with a predominant Th-1 response, which is associated with the most severe manifestations of H. pylori-induced gastric inflammation in humans (124, 165). It has also been reported that the immune responses to H. hepaticus infection in susceptible A/JCr and IL-10^−/− mice with chronic hepatitis and colitis, respectively, were consistent with a Th-1 phenotype (104, 183).

Much of the information on host immune responses to H. pylori infection in humans has been generated from investigations on chronically infected individuals. The availability of nonhuman primate models has, however, for the first time permitted workers to study host immune responses to acute helicobacter infection in an animal host closely related to humans. In the course of these investigations it was shown that rhesus monkeys, which were either helicobacter-free (89), or in which the natural helicobacter infection had been eliminated by antibiotic treatment (120), responded rapidly to an acute H. pylori infection by the production of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α (89, 120). Moreover, some monkeys became transiently infected after inoculation with H. pylori strains, and it was suggested that differences due to host genetic background, as well as bacterial strain-specific differences, may be important determinants in host susceptibility to H. pylori infection (29, 30).

Animal models have been instrumental in "proof of principle" studies concerning vaccination-mediated induction of host immunity against gastric Helicobacter infection (21, 27, 44, 51, 53, 123). Comparative immunological analyses of mice that developed a gastric Helicobacter infection, with those in which protective immunity had been generated by mucosal vaccination, have revealed interesting differences that may contribute to an improved understanding of the mechanisms involved in mucosal immunity to such infections (10, 54). The findings of these and other animal studies (44) have also challenged certain accepted dogmas of mucosal immunology. It is also becoming clear that the widely accepted Th-1/Th-2 paradigm may not fit so neatly with this type of mucosal infection (192).

Bacterial Pathogenesis Studies

A variety of bacterial factors have now been tested for their roles in gastric colonization using genetically engineered isogenic mutants (2, 9, 16, 32, 34, 80, 98, 121, 164). The roles of major colonization factors such as urease and flagellar-mediated motility were first confirmed in the gnotobiotic piglet model; indeed, bacterial challenge experiments showed that isogenic H. pylori mutants deficient in these properties could no longer colonize the animals (34, 37). Full motility in H. pylori was dependent on the expression of both FlaA and FlaB flagellins. Mutants defective in flagellin synthesis were subsequently generated in H. mustelae (2) and, more recently, in H. felis (98), and the role of Helicobacter motility for gastric colonization confirmed in ferret and murine hosts, respectively. Interestingly, it was observed that in the H. pylori/gnotobiotic pig and H. felis/mouse models, single-gene mutants were avirulent, whereas the equivalent mutants in H. mustelae were still able to establish a low level of colonization in the ferret. Similarly, conflicting findings have recently arisen from studies in which H. pylori mutants were tested in different animal models. Indeed, it was shown that H. pylori mutants deficient in γ-glutamyltranspeptidase and oxygen-insensitive NADPH nitroreductase activities, respectively, colonized animals to different degrees, depending not only on the type of animal host used (mouse versus Mongolian gerbil) (97), but also on the genetic background of the animal (Swiss outbred versus C57BL/6) (9, 16). This is a very significant observation that requires further clarification.

Conclusions

Animal models have played a critical role in many of the important discoveries in the Helicobacter field and have proven to be physiologically relevant to human Helicobacter disease. Although there is no single model that is the best for all applications, on the basis of cost and availability of immunological reagents and (soon) genome information, the mouse is undeniably the most convenient. For these reasons, inexperienced animal investigators are most likely to use mice as their animal model of choice for Helicobacter research. Nevertheless, there are many issues that need to be taken into consideration when establishing such models (Table 2).

The advent of small animal models permitting the establishment of chronic H. pylori infections associated with high levels of bacterial colonization and moderate-to-severe gastric inflammation opens the possibilities for investigators to pursue increasingly sophisticated studies on bacterial pathogenesis involving postgenomic techniques such as DNA microarray analysis. It should thus be possible to not only determine the Helicobacter gene products required for initial colonization, but also the temporal changes occurring in both host and pathogen gene expression in the course of the infection, and as a function of modifications in environmental or host factors.

Acknowledgments

We thank J. L. O'Rourke for providing high-quality electron photomicrographs and L. Ferrero for reading the manuscript and her support.

References

1.: Andersen L. P., Nørgaard A., Holck S., Blom J., Elsborg L. Isolation of a "Helicobacter heilmannii"-like organism from the human stomach. Eur. J. Clin. Microbiol. Infect. Dis. 1996;15:95–96. [PubMed: 8641315]
2.: Andrutis K. A., Fox J. G., Schauer D. B., Marini R. P., Li X., Yan L., Josenhans C., Suerbaum S. Infection of the ferret stomach by isogenic flagellar mutant strains of Helicobacter mustelae. Infect. Immun. 1997;65:1962–1966. [PMC free article: PMC175254] [PubMed: 9125590]
3.: Appelmelk B. J., Simoons-Smit I., Negrini R., Moran A. P., Aspinall G. O., Forte J. G., De Vries T., Quan H., Verboom T., Maaskant J. J., Ghiara P., Kuipers E. J., Bloemena E., Tadema T. M., Townsend R. R., Tyagarajan K., Crothers, Jr J. M., Monteiro M. A., Savio A., de Graft J. Potential role of molecular mimicry between Helicobacter pylori lipopolysaccharide and host Lewis blood group antigens in autoimmunity. Infect. Immun. 1996;64:2031–2040. [PMC free article: PMC174033] [PubMed: 8675304]
4.: Archer J. R., Romero S., Ritchie A. E., Hamacher M. E., Steiner B. M., Bryner J. H., Schell R. F. Characterization of an unclassified microaerophilic bacterium associated with gastroenteritis. J. Clin. Microbiol. 1988;26:101–105. [PMC free article: PMC266203] [PubMed: 3343302]
5.: Asahi M., Azuma T., Ito S., Ito Y., Suto H., Nagai Y., Tsubokawa M., Tohyama Y., Maeda S., Omata M., Suzuki T., Sasakawa C. Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells. J. Exp. Med. 2000;191:593–602. [PMC free article: PMC2195829] [PubMed: 10684851]
6.: Atherton J. C., Cao P., Peek R. M., Tummuru M. K. R., Blaser M. J., Cover T. L. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori: association of specific vacA types with cytotoxin production and peptic ulceration. J. Biol. Chem. 1995;270:1771–1777. [PubMed: 7629077]
7.: Berg D. J., Lynch N. A., Lynch R. G., Lauricella D. M. Rapid development of severe hyperplastic gastritis with gastric epithelial dedifferentiation in Helicobacter felis-infected IL-10^−/− mice. Am. J. Pathol. 1998;152:1377–1386. [PMC free article: PMC1858590] [PubMed: 9588906]
8.: Bizzozeroni G. Über die schlauchförmigen Drusen des Magendarmkanals und die Beziehungen ihres Epithels zu dem Oberfachenepithel der Schleimhaut. Arch. Mikrobiol. Anat. 1892;42:82–152.
9.: Blanchard T. G., McGovern K. J., Youngman P., Gutierez J., Czinn S. J. Is gamma-glutamyl transpeptidase essential for infection of the gastric mucosa by H. pylori? Gut. 1999;45:A26.
10.: Blanchard T. G., Nedrud J. G., Reardon E. S., Czinn S. J. Qualitative and quantitative analysis of the local and systemic antibody response in mice and humans with Helicobacter immunity and infection. J. Infect. Dis. 1999;179:725–728. [PubMed: 9952387]
11.: Bliss C. M. J., Golenbock D. T., Keates S., Linevsky J. K., Kelly C. P. Helicobacter pylori lipopolysaccharide binds to CD14 and stimulates release of interleukin-8, epithelial neutrophil-activating peptide 78, and monocyte chemotactic protein 1 by human monocytes. Infect. Immun. 1998;66:5357–5363. [PMC free article: PMC108670] [PubMed: 9784544]
12.: Bronsdon M. A., Goodwin C. S., Sly L. I., Chilvers T., Schoenknecht F. D. Helicobacter nemestrinae sp. nov., a spiral bacterium found in the stomach of a pigtailed Macaque (Macaca nemestrina). Int. J. Syst. Bacteriol. 1991;41:148–153. [PubMed: 1995031]
13.: Cahill R. J., Foltz C. J., Fox J. G., Dangler C. A., Powrie F., Schauer D. B. Inflammatory bowel disease: an immune mediated condition triggered by bacterial infection with Helicobacter hepaticus. Infect. Immun. 1997;65:3126–3131. [PMC free article: PMC175441] [PubMed: 9234764]
14.: Cantorna M. T., Balish E. Inability of human clinical strains of Helicobacter pylori to colonize the alimentary tract of germfree rodents. Can. J. Microbiol. 1990;36:237–241. [PubMed: 2357642]
15.: Censini S., Lange C., Xiang Z., Crabtree J. E., Ghiara P., Borodovsky M., Rappuoli R., Covacci A. cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc. Natl. Acad. Sci. USA. 1996;93:14648–14653. [PMC free article: PMC26189] [PubMed: 8962108]
16.: Chevalier C., Thiberge J.-M., Ferrero R. L., Labigne A. Essential role of Helicobacter pylori γ-glutamyltranspeptidase for the colonization of the gastric mucosa of mice. Mol. Microbiol. 1999;31:1359–1372. [PubMed: 10200957]
17.: Chien C.-C., Taylor N. S., Ge Z., Schauer D. B., Young V. B., Fox J. G. Identification of cdtB homologues and cytolethal distending toxin activity in enterohepatic Helicobacter spp. Med. Microbiol. 2000;49:525–534. [PubMed: 10847206]
18.: Correa P. Human gastric carcinogenesis: a multistep and multifactorial process. First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 1992;52:6735–6740. [PubMed: 1458460]
19.: Cover T. L., Blaser M. J. Purification and characterization of the vacuolating toxin from Helicobacter pylori. J. Biol. Chem. 1992;267:10570–10575. [PubMed: 1587837]
20.: Crabtree J. E., Covacci A., Farmery S. M., Xiang Z., Tompkins D. S., Perry S., Lindley I. J. D., Rappuoli R. Helicobacter pylori induced interleukin-8 expression in gastric epithelial cells is associated with CagA positive phenotype. J. Clin. Pathol. 1995;48:41–45. [PMC free article: PMC502260] [PubMed: 7706517]
21.: Czinn S. J., Cai A., Nedrud J. G. Protection of germ-free mice from infection by Helicobacter felis after active oral or passive IgA immunization. Vaccine. 1993;11:637–642. [PubMed: 8322486]
22.: De Magalha ¯ es Queiroz D. M., Aguiar Rocha G., Nogueira Mendes E., Beleza de Moura S., Rocha de Oliveira A. M., Miranda D. Association between Helicobacter and gastric ulcer disease of the pars esophagea in swine. Gastroenterology. 1996;111:19–27. [PubMed: 8698198]
23.: Dewhirst, F. E., and J. G. Fox. 2000. Unpublished data.
24.: Dewhirst F. E., Fox J. G., Mendes E. N., Paster B. J., Gates C. E., Kirkbride C. A., Eaton K. A. `Flexispira rappini' strains represent at least 10 Helicobacter taxa. Int. J. System. Bacteriol. Evol. Microbiol. 2000;50:1781–1787. [PubMed: 11034487]
25.: Dick-Hegedus E., Lee A. Use of a mouse model to examine anti-Helicobacter pylori agents. Scand. J. Gastroenterol. 1991;26:909–915. [PubMed: 1947781]
26.: Doenges J. L. Spirochetes in the gastric glands of Macacus rhesus and of man without related disease. Arch. Pathol. 1939;27:469–477.
27.: Doidge C., Gust I., Lee A., Buck F., Hazell S., Manne U. Therapeutic immunisation against helicobacter infection. Lancet. 1994;343:914–915. [PubMed: 7908372]
28.: Drazek E. S., Dubois A., Holmes R. K. Characterization and presumptive identification of Helicobacter pylori isolates from rhesus monkeys. J. Clin. Microbiol. 1994;32:1799–1804. [PMC free article: PMC263799] [PubMed: 7523441]
29.: Dubois A., Berg D. E., Incecik E. T., Fiala N., Heman-Ackah L. M., Del Valle J., Yang M., Wirth H.-P., Pérez-Pérez G. I., Blaser M. J. Host specificity of Helicobacter pylori strains and host responses in experimentally challenged non-human primates. Gastroenterology. 1999;116:90–96. [PubMed: 9869606]
30.: Dubois A., Berg D. E., Incecik E. T., Fiala N., Heman-Ackah L. M., Perez-Perez G. I., Blaser M. J. Transient and persistent experimental infection of nonhuman primates with Helicobacter pylori: implications for human disease. Infect. Immun. 1996;64:2885–2891. [PMC free article: PMC174162] [PubMed: 8757808]
31.: Dubois A., Fiala N., Heman-Ackah L. M., Drazek E. S., Tarnawski A., Fishbein W. N., Perez-Perez G. I., Blaser M. J. Natural gastric infection with Helicobacter pylori in monkeys: a model for spiral bacteria infection in humans. Gastroenterology. 1994;106:1405–1417. [PubMed: 8194685]
32.: Eaton K. A., Cover T. L., Tummuru M. K. R., Blaser M. J., Krakowka S. Role of vacuolating cytotoxin in gastritis due to Helicobacter pylori in gnotobiotic piglets. Infect. Immun. 1997;65:3462–3464. [PMC free article: PMC175490] [PubMed: 9234813]
33.: Eaton K. A., Dewhirst F. E., Paster B. J., Tzellas N., Coleman B. E., Paola J., Sherding R. Prevalence and varieties of Helicobacter species in dogs from random sources and pet dogs: animal and public health implications. J. Clin. Microbiol. 1996;34:3165–3170. [PMC free article: PMC229476] [PubMed: 8940465]
34.: Eaton K. A., Krakowka S. Effect of gastric pH on urease-dependent colonization of gnotobiotic piglets by Helicobacter pylori. Infect. Immun. 1994;62:3604–3607. [PMC free article: PMC303008] [PubMed: 8063376]
35.: Eaton K. A., Radin M. J., Krakowka S. Animal models of bacterial gastritis: the role of host, bacterial species and duration of infection on severity of gastritis. Zentralbl. Bakteriol. 1993;280:28–37. [PubMed: 8280953]
36.: Eaton K. A., Ringler S. R., Danon S. J. Murine splenocytes induce severe gastritis and delayed-type hypersensitivity and suppress bacterial colonization in Helicobacter pylori-infected SCID mice. Infect. Immun. 1999;67:4594–4602. [PMC free article: PMC96783] [PubMed: 10456905]
37.: Eaton K. A., Suerbaum S., Josenhans C., Krakowka S. Colonisation of gnotobiotic piglets by Helicobacter pylori deficient in two flagellin genes. Infect. Immun. 1996;64:2445–2448. [PMC free article: PMC174096] [PubMed: 8698465]
38.: El-Omar E. M., Carrington M., Chow W.-H., McColl K. E. L., Bream J. H., Young H. A., Herrera J., Lissowska J., Yuan C.-C., Rothman N., Lanyon G., Martin M., Fraumeni J. F. J., Rabkin C. S. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404:398–402. [PubMed: 10746728]
39.: Elwell C. A., Dreyfus L. A. DNase I homologous residues in CdtB are critical for cytolethal distending toxin-mediated cell cycle arrest. Mol. Microbiol. 2000;37:952–963. [PubMed: 10972814]
40.: Enders G., Brooks W., von Jan N., Lehn N., Bayerdörffer E., Hatz R. Expression of adhesion molecules on human granulocytes after stimulation with Helicobacter pylori membrane antigens: comparison with membrane proteins from other bacteria. Infect. Immun. 1995;63:2473–2477. [PMC free article: PMC173330] [PubMed: 7540595]
41.: Enno A., O'Rourke J. L., Braye S., Howlett C. R., Lee A. Antigen-dependent progression of mucosa-associated lymphoid tissue (MALT)-type lymphoma in the stomach. Am. J. Pathol. 1998;152:1625–1632. [PMC free article: PMC1858462] [PubMed: 9626066]
42.: Enno A., O'Rourke J. L., Howlett C. R., Jack A., Dixon M. F., Lee A. MALToma-like lesions in the murine gastric mucosa after long-term infection with Helicobacter felis. Am. J. Pathol. 1995;147:217–222. [PMC free article: PMC1869885] [PubMed: 7604881]
43.: Erdman S. E., Correa P., Coleman L. A., Schrenzel M. D., Li X., Fox J. G. Helicobacter mustelae-associated gastric MALT lymphoma in ferrets. Am. J. Pathol. 1997;151:273–280. [PMC free article: PMC1857920] [PubMed: 9212752]
44.: Ermak T. H., Giannasca P. J., Nichols R., Myers G. A., Nedrud J., Weltzin R., Lee C. K., Kleanthous H., Monath T. P. Immunization of mice with urease vaccine affords protection against Helicobacter pylori infection in the absence of antibodies and is mediated by MHC class II-restricted responses. J. Exp. Med. 1998;188:1–12. [PMC free article: PMC2212427] [PubMed: 9858514]
45.: Esteves M. I., Schrenzel M. D., Marini R. P., Taylor N. S., Xu S., Hagen S., Feng Y., Shen Z., Fox J. G. Helicobacter pylori gastritis in cats with long term natural infection as a model of human disease. Am. J. Pathol. 2000;156:709–721. [PMC free article: PMC1850051] [PubMed: 10666399]
46.: Evans D. J., Evans D. G., Takemura T., Nakano H., Lampert H. C., Graham D. Y., Granger D. N., Kvietys P. R. Characterization of a Helicobacter pylori neutrophil-activating protein. Infect. Immun. 1995;63:2213–2220. [PMC free article: PMC173288] [PubMed: 7768601]
47.: Fennell C. L., Totten P. A., Quinn T. C., Patton D. L., Holmes K. K., Stamm W. E. Characterization of Campylobacter-like organisms isolated from homosexual men. J. Infect. Dis. 1984;149:58–66. [PubMed: 6693790]
48.: Ferrero, R. L. 1998. Unpublished data.
49.: Ferrero R. L., Avé P., Radcliff F. J., Labigne A., Huerre M.-R. Outbred mice with long-term Helicobacter felis infection develop both gastric lymphoid tissue and glandular hyperplastic lesions. J. Pathol. 2000;191:333–340. [PubMed: 10878557]
50.: Ferrero, R. L., I. N. Kansau, and A. Labigne. 1997. Virulence factors produced by H. pylori, p. 29–45. In P. Ernst, P. Michetti, and P. D. Smith (ed.), The Immunobiology of H. pylori: from Pathogenesis to Prevention. Lippincott-Raven Publishers, Philadelphia, Pa.
51.: Ferrero R. L., Thiberge J.-M., Huerre M., Labigne A. Recombinant antigens prepared from the urease subunits of Helicobacter spp.: evidence of protection in a mouse model of gastric infection. Infect. Immun. 1994;62:4981–4989. [PMC free article: PMC303216] [PubMed: 7927778]
52.: Ferrero R. L., Thiberge J. M., Huerre M., Labigne A. Immune responses of specific-pathogen-free mice to chronic Helicobacter pylori (strain SS1) infection. Infect. Immun. 1998;66:1349–1355. [PMC free article: PMC108059] [PubMed: 9529052]
53.: Ferrero R. L., Thiberge J.-M., Kansau I., Wuscher N., Huerre M., Labigne A. The GroES homolog of Helicobacter pylori confers protective immunity against mucosal infection in mice. Proc. Natl. Acad. Sci. USA. 1995;92:6499–6503. [PMC free article: PMC41545] [PubMed: 7604021]
54.: Ferrero R. L., Thiberge J.-M., Labigne A. Local immunoglobulin G antibodies in the stomach may contribute to immunity against Helicobacter infection in mice. Gastroenterology. 1997;113:185–194. [PubMed: 9207277]
55.: Figura N., Guglielmetti P., Rossolini A., Barberi A., Cusi G., Musmanno R. A., Russi M., Quaranta S. Cytotoxin production by Campylobacter pylori strains isolated from patients with peptic ulcers and from patients with chronic gastritis only. J. Clin. Microbiol. 1989;27:225–226. [PMC free article: PMC267274] [PubMed: 2913034]
56.: Foley J. E., Marks S., Munson L., Melli A., Dewhirst D. E., Yu S., Shen Z., Fox J. G. Isolation of Helicobacter canis from a colony of Bengal cats with endemic diarrhea. J. Clin. Microbiol. 1999;37:3271–3275. [PMC free article: PMC85546] [PubMed: 10488191]
57.: Foltz C., Fox J. G., Yan L., Shames B. Evaluation of antibiotic therapies for the eradication of Helicobacter hepaticus. Antimicrob. Agents Chemother. 1995;36:1292–1294. [PMC free article: PMC162729] [PubMed: 7574518]
58.: Foltz C. J., Fox J. G., Cahill R. J., Murphy R. C., Yan L., Shames B., Schauer D. B. Spontaneous inflammatory bowel disease in multiple mutant mouse lines: association with colonization by Helicobacter hepaticus. Helicobacter. 1998;3:69–78. [PubMed: 9631303]
58a.: Fox J. G., Batchelder M., Marini R., Yan L., Handt L., Li X., Shames B., Hayward A., Campbell J., Murphy J. C. Helicobacter pylori-induced gastritis in the domestic cat. Infect. Immun. 1995;63:2674–2681. [PMC free article: PMC173358] [PubMed: 7790084]
59.: Fox J. G., Beck P., Dangler C. A., Whary M. T., Wang T. C., Shi H. N., Nagler-Anderson C. Concurrent enteric helminth infection modulates inflammation, gastric immune responses, and reduces helicobacter-induced gastric atrophy. Nat. Med. 2000;6:536–542. [PubMed: 10802709]
60.: Fox J. G., Chien C. C., Dewhirst F. E., Paster B. J., Shen Z., Melito P. L., Woodward D. L., Rodgers F. G. Helicobacter canadensis sp. nov. isolated from humans with diarrhea: an example of an emerging pathogen. J. Clin. Microbiol. 2000;38:2546–2549. [PMC free article: PMC86964] [PubMed: 10878041]
61.: Fox J. G., Correa P., Taylor N. S., Lee A., Otto G., Murphy J. C., Rose R. Helicobacter mustelae associated gastritis in ferrets: an animal model of Helicobacter pylori gastritis in humans. Gastroenterology. 1990;99:352–361. [PubMed: 2365188]
62.: Fox J. G., Dangler C. A., Taylor N. S., King A., Koh T., Wang T. High salt diet induces gastric epithelial hyperplasia, parietal cell loss, and enhances Helicobacter pylori colonization in C57BL/6 mice. Cancer Res. 1999;59:4823–4828. [PubMed: 10519391]
63.: Fox J. G., Dangler C. A., Whary M. T., Edelman W., Kucherlapati R., Wang T. C. Mice carrying a truncated Apc gene have diminished gastric epithelial proliferation, gastric inflammation, and humoral immunity in response to Helicobacter felis infection. Cancer Res. 1997;57:3972–3978. [PubMed: 9307281]
64.: Fox J. G., Dewhirst F. E., Shen Z., Fen Y., Taylor N. S., Paster B., Erickson R. L., Lau C. N., Correa P., Araya J. C., Roa I. Hepatic Helicobacter species identified in bile and gallbladder tissue from Chileans with chronic cholecystitis. Gastroenterology. 1998;114:755–763. [PubMed: 9516396]
65.: Fox J. G., Dewhirst F. E., Tully J. G., Paster B. J., Yan L., Taylor N. S., Collins, Jr M. J., Gorelick P. L., Ward J. M. Helicobacter hepaticus sp. nov., a microaerophilic bacterium isolated from livers and intestinal mucosal scrapings from mice. J. Clin. Microbiol. 1994;32:1238–1245. [PMC free article: PMC263656] [PubMed: 8051250]
66.: Fox J. G., Drolet R., Higgins R., Messier S., Yan L., Coleman B. E., Paster B. J., Dewhirst F. E. Helicobacter canis isolated from a dog liver with multifocal necrotizing hepatitis. J. Clin. Microbiol. 1996;34:2479–2482. [PMC free article: PMC229299] [PubMed: 8880504]
67.: Fox J. G., Edrise B. M., Cabot E. B., Beaucage C., Murphy J. C., Prostak K. S. Campylobacter-like organisms isolated from the gastric mucosa of ferrets. Am. J. Vet. Res. 1986;47:236–239. [PubMed: 3954197]
68.: Fox J. G., Gorelick P. L., Kullberg M. C., Ge Z., Dewhirst F. E., Ward J. M. A novel urease-negative Helicobacter species associated with colitis and typhlitis in IL-10-deficient mice. Infect. Immun. 1999;67:1757–1762. [PMC free article: PMC96525] [PubMed: 10085015]
69.: Fox J. G., Lee A. The role of Helicobacter species in newly recognized gastrointestinal tract diseases of animals. Lab. Anim. Sci. 1997;47:222–255. [PubMed: 9241625]
70.: Fox J. G., Lee A., Otto G., Taylor N. S., Murphy J. C. Helicobacter felis gastritis in gnotobiotic rats: an animal model of Helicobacter pylori gastritis. Infect. Immun. 1991;59:785–791. [PMC free article: PMC258328] [PubMed: 1997430]
71.: Fox J. G., Li X., Cahill R., Andrutis K., Rustgi A. K., Odze R., Wang T. C. Hypertrophic gastropathy in Helicobacter felis-infected wild-type C57BL/6 and p53 hemizygous transgenic mice. Gastroenterology. 1996;110:155–166. [PubMed: 8536852]
72.: Fox J. G., Li X., Yan L., Cahill R. J., Hurley R., Lewis R., Murphy J. C. Chronic proliferative hepatitis in A/JCr mice associated with persistent Helicobacter hepaticus infection: a model of Helicobacter-induced carcinogenesis. Infect. Immun. 1996;64:1548–1558. [PMC free article: PMC173960] [PubMed: 8613359]
73.: Fox J. G., Murphy B. M. J. C., Taylor N. S., Lee A., Kabok Z., Pappo J. Local and systemic immune responses in murine Helicobacter felis active chronic gastritis. Infect. Immun. 1993;61:2309–2315. [PMC free article: PMC280850] [PubMed: 8500873]
74.: Fox J. G., Perkins S., Yan L., Shen Z., Attardo L., Pappo J. Local immune response in Helicobacter pylori infected cats and identification of H. pylori in saliva, gastric fluid and feces. Immunology. 1996;88:400–406. [PMC free article: PMC1456360] [PubMed: 8774357]
75.: Fox J. G., Yan L. L., Dewhirst F. E., Paster B. J., Shames B., Murphy J. C., Hayward A., Belcher J. C., Mendes E. N. Helicobacter bilis sp. nov., a novel helicobacter isolated from bile, livers, and intestines of aged, inbred mice. J. Clin. Microbiol. 1995;33:445–454. [PMC free article: PMC227964] [PubMed: 7536217]
76.: Franklin C. L., Beckwith C. S., Livingston R. S., Riley L. K., Gibson S. V., Besch-Williford C. L., Hook, Jr R. R. Isolation of a novel Helicobacter species, Helicobacter cholecystus sp. nov., from the gallbladders of Syrian hamsters with cholangiofibrosis and centrilobular pancreatitis. J. Clin. Microbiol. 1996;34:2952–2958. [PMC free article: PMC229440] [PubMed: 8940429]
77.: Franklin C. L., Riley L. K., Livingston R. S., Beckwith C. S., Besch-Williford C., Hook, Jr R. R. Enterohepatic lesions in SCID mice infected with Helicobacter bilis. Lab. Anim. Sci. 1998;48:334–339. [PubMed: 10090038]
78.: Franklin C. L., Riley L. K., Livingston R. S., Beckwith C. S., Hook, Jr R. R., Besch-Williford C., Huziker R., Gorelick P. L. Enteric lesions in SCID mice infected with "Helicobacter typhlonicus," a novel urease-negative Helicobacter species. Lab. Anim. Sci. 1999;49:496–505. [PubMed: 10551450]
79.: Freedberg A. S., Barron L. E. The presence of spirochetes in human gastric mucosa. Am. J. Dig. Dis. 1940;7:443–445.
80.: Ge Z., Feng Y., Dangler C. A., Xu S., Taylor N. S., Fox J. G. Fumarate reductase is essential for Helicobacter pylori colonization of the mouse stomach. Microb. Pathog. 2000;29:279–287. [PubMed: 11031122]
81.: Gebhart C. J., Fennell C. L., Murtaugh M. P., Stamm W. E. Campylobacter cinaedi is normal intestinal flora in hamsters. J. Clin. Microbiol. 1989;27:1692–1694. [PMC free article: PMC267646] [PubMed: 2768458]
82.: Gerhard M., Lehn N., Neumayer N., Borén T., Rad R., Schepp W., Miehlke S., Classen M., Prinz C. Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesin. Proc. Natl. Acad. Sci. USA. 1999;96:12778–12783. [PMC free article: PMC23096] [PubMed: 10535999]
83.: Goodwin C. S., Armstrong J. A., Chilvers T., Peters M., Collins M. D., Sly L., McConnell W., Harper W. E. S. Transfer of Campylobacter pylori and Campylobacter mustelae to Helicobacter gen. nov. as Helicobacter pylori comb. nov. and Helicobacter mustelae comb. nov., respectively. Int. J. Syst. Bacteriol. 1989;39:397–405.
84.: Greiner A., Knör C., Qin Y., Sebald W., Schimpl A., Banchereau J., Müller-Hermelink H. K. Low-grade B cell lymphomas of mucosa-associated lymphoid tissue (MALT-type) require CD40-mediated signaling and Th2-type cytokines for in vitro growth and differentiation. Am. J. Pathol. 1997;150:1583–1593. [PMC free article: PMC1858212] [PubMed: 9137085]
85.: Guruge J. L., Falk P. G., Lorenz R. G., Dans M., Wirth H.-P., Blaser M. J., Berg D. E., Gordon J. L. Epithelial attachment alters the outcome of Helicobacter pylori infection. Proc. Natl. Acad. Sci. USA. 1998;95:3925–3930. [PMC free article: PMC19939] [PubMed: 9520469]
86.: Hänninen M.-L., Happonen I., Saari S., Jalava K. Culture and characteristics of Helicobacter bizzozeronii, a new canine gastric Helicobacter sp. Int. J. Syst. Bacteriol. 1996;46:160–166. [PubMed: 8573490]
87.: Happonen I., Saari S., Castren L., Tyni O., Hänninen M.-L., Westermarck E. Occurrence and topological mapping of gastric Helicobacter-like organisms and their association with histological changes in apparently healthy dogs and cats. J. Vet. Med. 1996;43:305–315. [PubMed: 8779805]
88.: Harris P. R., Mobley H. L. T., Pérez-Pérez G. I., Blaser M. J., Smith P. D. Helicobacter pylori urease is a potent stimulus of mononuclear phagocyte activation and inflammatory cytokine production. Gastroenterology. 1996;111:419–425. [PubMed: 8690207]
89.: Harris P. R., Smythies L. E., Smith P. D., Dubois A. Inflammatory cytokine mRNA expression during early and persistent Helicobacter pylori infection in nonhuman primates. J. Infect. Dis. 2000;181:783–786. [PubMed: 10669377]
90.: Heilmann K. L., Borchard F. Gastritis due to spiral shaped bacteria other than Helicobacter pylori: clinical, histological, and ultrastructural findings. Gut. 1991;32:137–140. [PMC free article: PMC1378794] [PubMed: 1864530]
91.: Hermanns W., Kregel K., Breuer W., Lechner J. Helicobacter-like organisms: histopathological examination of gastric biopsies from dogs and cats. J. Comp. Pathol. 1995;112:307–318. [PubMed: 7560305]
92.: Ihrig M., Schrenzel M., Fox J. G. Differential susceptibility to hepatic inflammation and proliferation in AXB recombinant inbred mice chronically infected with Helicobacter hepaticus. Am. J. Pathol. 1999;155:571–582. [PMC free article: PMC1868606] [PubMed: 10433949]
93.: Ikeno T., Ota H., Sugiyama A., Ishida K., Katsuyama T., Genta R. M., Kawasaki S. Helicobacter pylori-induced chronic active gastritis, intestinal metaplasia, and gastric ulcer in Mongolian gerbils. Am. J. Pathol. 1999;154:951–960. [PMC free article: PMC1866409] [PubMed: 10079274]
94.: Jalava K., Kaartinen M., Utriainen M., Happonen I., Hänninen M.-L. Helicobacter salomonis sp. nov., a canine gastric Helicobacter sp. related to Helicobacter felis and Helicobacter bizzozeronii. Int. J. Syst. Bacteriol. 1997;47:975–982. [PubMed: 9336895]
95.: Jenks P. J., Ferrero R. L., Labigne A. The role of the rdxA gene in the evolution of metronidazole resistance in Helicobacter pylori. J. Antimicrob. Chemother. 1999;43:753–758. [PubMed: 10404313]
96.: Jenks P. J., Labigne A., Labigne R. L. Exposure to metronidazole in vivo readily induces resistance in Helicobacter pylori and reduces the efficacy of eradication therapy in mice. Antimicrob. Agents Chemother. 1999;43:777–781. [PMC free article: PMC89206] [PubMed: 10103180]
97.: Jeong, J. Y., A. K. Mukhopadhyay, W. W. Su, P. S. Hoffman, and D. E. Berg. 2000. Interplay of bacterial genetic background and host genotype or physiology determines the actual cost of metronidazole resistance for Helicobacter pylori, abstr. D-277, p. 290. In Abstr. 100th Gen. Meet. Am. Soc. Microbiol. 2000. American Society for Microbiology, Washington, D.C.
98.: Josenhans C., Ferrero R. L., Labigne A., Suerbaum S. Cloning and allelic exchange mutagenesis of two flagellin genes of Helicobacter felis. Mol. Microbiol. 1999;33:350–362. [PubMed: 10411751]
99.: Karita M., Kouchiyama T., Okita K., Nakazawa T. New small animal model for human gastric Helicobacter pylori infection: success in both nude and euthymic mice. Am. J. Gastroenterol. 1991;11:1596–1603. [PubMed: 1951236]
100.: Keates S., Hitti Y. S., Upton M., Kelly C. P. Helicobacter pylori infection activates NF-κB in gastric epithelial cells. Gastroenterology. 1997;113:1099–1109. [PubMed: 9322504]
101.: Krakowka S., Eaton K. A., Leunk R. D. Antimicrobial therapies for Helicobacter pylori infection in gnotobiotic piglets. Antimicrob. Agents Chemother. 1998;42:1549–1554. [PMC free article: PMC105643] [PubMed: 9660981]
102.: Krakowka S., Eaton K. A., Rings D. M. Occurrence of gastric ulcers in gnotobiotic piglets colonized by Helicobacter pylori. Infect. Immun. 1995;63:2352–2355. [PMC free article: PMC173310] [PubMed: 7768620]
103.: Krakowka S., Morgan D. R., Kraft W. G., Leunk R. D. Establishment of gastric Campylobacter pylori infection in the neonatal gnotobiotic piglet. Infect. Immun. 1987;55:2789–2796. [PMC free article: PMC259978] [PubMed: 3666963]
104.: Kullberg M. C., Ward J. M., Gorelick P. L., Caspar P., Hieny S., Cheever A., Jankovic D., Sher A. Helicobacter hepaticus triggers colitis in specific-pathogen-free interleukin-10 (IL-10)-deficient mice through an IL-12 and gamma interferon-dependent mechanism. Infect. Immun. 1998;66:5157–5166. [PMC free article: PMC108643] [PubMed: 9784517]
105.: Lee A., Chen M., Coltro N., O'Rourke J., Hazell S., Hu P., Li Y. Long term infection of the gastric mucosa with Helicobacter species does induce atrophic gastritis in an animal model of Helicobacter pylori infection. Zentralbl. Bakteriol. 1993;280:38–50. [PubMed: 8280955]
106.: Lee A., Dent J., Hazell S., McNulty C. Origin of spiral organisms in human gastric antrum. Lancet. 1988;i:300–301. [PubMed: 2893112]
107.: Lee, A., and J. Fox. 1991. Helicobacter pylori and other gastric spirilla: similarities and differences, p. 54–62. In H. Menge, M. Gregor, G. N. J. Tytgat, B. J. Marshall, and C. A. M. McNulty (ed.), Helicobacter pylori 1990. Berlin, Germany.
108.: Lee A., Fox J. G., Otto G., Murphy J. A small animal model of human Helicobacter pylori active chronic gastritis. Gastroenterology. 1990;99:1315–1325. [PubMed: 2210240]
109.: Lee A., Hazell S. L., O'Rourke J., Kouprach S. Isolation of a spiral-shaped bacterium from the cat stomach. Infect. Immun. 1988;56:2843–2850. [PMC free article: PMC259659] [PubMed: 3169989]
110.: Lee A., Krakowka S., Fox J. G., Otto G., Eaton K. A., Murphy J. C. Role of Helicobacter felis in chronic gastritis of the canine stomach. Vet. Pathol. 1992;29:487–492. [PubMed: 1448894]
111.: Lee A., O'Rourke J., De Ungria M. C., Robertson B., Daskalopoulos G., Dixon M. F. A standardized mouse model of Helicobacter pylori infection: introducing the Sydney strain. Gastroenterology. 1997;112:1386–1397. [PubMed: 9098027]
112.: Lee A., Phillips M. W., O'Rourke J. L., Paster B. J., Dewhirst F. E., Fraser G. J., Fox J. G., Sly L. I., Romaniuk P. J., Trust T. J., Kouprach S. Helicobacter muridarum sp. nov., a microaerophilic helical bacterium with a novel ultrastructure isolated from the intestinal mucosa of rodents. Int. J. Syst. Bacteriol. 1992;42:27–36. [PubMed: 1736969]
113.: Letley D. P., Atherton J. C. Natural diversity in the N terminus of the mature vacuolating cytotoxin of Helicobacter pylori determines cytotoxin activity. J. Bacteriol. 2000;182:3278–3280. [PMC free article: PMC94518] [PubMed: 10809711]
114.: Leunk R. D., Johnson P. T., David B. C., Kraft W. G., Morgan D. R. Cytotoxic activity in broth-culture filtrates of Campylobacter pylori. J. Med. Microbiol. 1988;26:93–99. [PubMed: 3385767]
115.: Mai U. E. H., Perez-Perez G. I., Allen J. B., Wahl S. M., Blaser M. J., Smith P. D. Surface proteins from Helicobacter pylori exhibit chemotactic activity for human leukocytes and are present in gastric mucosa. J. Exp. Med. 1992;175:517–525. [PMC free article: PMC2119134] [PubMed: 1732414]
116.: Mai U. E. H., Pérez-Pérez G. I., Wahl L. M., Wahl S. M., Blaser M. J., Smith P. D. Soluble surface proteins from Helicobacter pylori activate monocytes/macrophages by lipopolysaccharide-independent mechanism. J. Clin. Invest. 1991;87:894–900. [PMC free article: PMC329879] [PubMed: 1847939]
117.: Marchetti M., Arico B., Burroni D., Figura N., Rappuoli R., Ghiara P. Development of a mouse model of Helicobacter pylori infection that mimics human disease. Science. 1995;267:1655–1658. [PubMed: 7886456]
118.: Marshall B. J., Warren J. R. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984;i:1311–1315. [PubMed: 6145023]
119.: Matsumoto S., Washizuka Y., Matsumoto Y., Tawara S., Ikeda F., Yokota Y., Karita M. Induction of ulceration and severe gastritis in Mongolian gerbil by Helicobacter pylori infection. J. Med. Microbiol. 1997;46:391–397. [PubMed: 9152034]
120.: Mattapallil J. J., Dandekar S., Canfield D. R., Solnick J. V. A predominant Th1 type of immune response is induced early during acute Helicobacter pylori infection in rhesus macaques. Gastroenterology. 2000;118:307–315. [PubMed: 10648459]
121.: McGee D. J., Radcliff F. J., Mendz G. L., Ferrero R. L., Mobley H. L. T. Helicobacter pylori rocF is required for arginase activity and acid protection in vitro but is not essential for colonization of mice or for urease activity. J. Bacteriol. 1999;181:7314–7322. [PMC free article: PMC103695] [PubMed: 10572136]
122.: Mendes E. N., Queiroz D. M. M., Dewhirst F. E., Paster B. J., Moura S. B., Fox J. G. Helicobacter trogontum sp. nov., isolated from the rat intestine. Int. J. Syst. Bacteriol. 1996;46:916–921. [PubMed: 8863417]
123.: Michetti P., Corthésy-Theulaz I., Davin C., Haas R., Vaney A.-C., Heitz M., Bille J., Kraehenbuhl J.-P., Saraga E., Blum A. I. Immunization of Balb/c mice against Helicobacter felis infection with Helicobacter pylori urease. Gastroenterology. 1994;107:1002–1011. [PubMed: 7926454]
124.: Mohammadi M., Czinn S., Redline R., Nedrud J. Helicobacter-specific cell-mediated immune responses display a predominant Th1 phenotype and promote a delayed-type hypersensitive response in the stomachs of mice. J. Immunol. 1996;156:4729–4738. [PubMed: 8648119]
125.: Mohammadi M., Redline R., Nedrud J., Czinn S. Role of the host in pathogenesis of Helicobacter-associated gastritis: H. felis infection of inbred and congenic mouse strains. Infect. Immun. 1996;64:238–245. [PMC free article: PMC173751] [PubMed: 8557346]
126.: Molinari M., Galli C., Norais N., Telford J., Rappuoli R., Luzio J., Montecucco C. Vacuoles induced by Helicobacter pylori toxin contain both late endosomal and lysosomal markers. J. Biol. Chem. 1997;272:25339–25344. [PubMed: 9312153]
127.: Monteiro M. A., Zheng P. Y., Appelmelk B. J., Perry M. B. The lipopolysaccharide of Helicobacter mustelae type strain ATCC 43772 expresses the monofucosyl A type 1 histoblood group epitope. FEMS Microbiol. Lett. 1997;154:103–109. [PubMed: 9297827]
128.: Morgan D. R., Fox J. G., Leunk R. D. Comparison of isolates of Helicobacter pylori and Helicobacter mustelae. J. Clin. Microbiol. 1991;29:395–397. [PMC free article: PMC269775] [PubMed: 2007648]
129.: Morgner A., Lehn N., Andersen L. P., Thiede C., Bennedsen M., Trebesius K., Neubauer B., Neubauer A., Stolte M., Bayerdörffer Helicobacter heilmannii-associated primary gastric low-grade MALT lymphoma: complete remission after curing the infection. Gastroenterology. 2000;118:821–828. [PubMed: 10784580]
130.: Moura S. B., Queiroz D. M. M., Mendes E. N., Nogueira A. M. M. F., Rocha G. A. The inflammatory response of the gastric mucosa of mice experimentally infected with "Gastrospirillum suis. J. Med. Microbiol. 1993;39:64–68. [PubMed: 8326514]
131.: Münzenmaier A., Lange C., Glocker E., Covacci A., Moran A., Bereswill S., Baeurle P. A., Kist M., Pahl H. L. A secreted/shed product of Helicobacter pylori activates transcription factor nuclear factor-κB. J. Immunol. 1997;159:6140–6147. [PubMed: 9550415]
132.: Muotiala A., Helander I. M., Pyhälä L., Kosunen T. U., Moran A. P. Low biological activity of Helicobacter pylori lipopolysaccharide. Infect. Immun. 1992;60:1714–1716. [PMC free article: PMC257055] [PubMed: 1548097]
133.: Neiger R., Dieterich C., Burnens A., Waldvogel A., Corthésy-Theulaz I., Halter F., Lauterburg B., Schmassmann A. Detection and prevalence of Helicobacter infection in pet cats. J. Clin. Microbiol. 1998;36:634–637. [PMC free article: PMC104599] [PubMed: 9508286]
134.: Nomura A., Stemmermann G. N., Chyou P. H., Kato I., Perez-Perez G. I., Blaser M. J. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N. Engl. J. Med. 1991;325:1132–1136. [PubMed: 1891021]
135.: Norris C. R., Marks S. L., Eaton K. A., Torabian S. Z., Munn R. J., Solnick J. V. Healthy cats are commonly colonized with "Helicobacter heilmannii" that is associated with minimal gastritis. J. Clin. Microbiol. 1999;37:189–194. [PMC free article: PMC84203] [PubMed: 9854088]
136.: O. Cróinin T., Clyne M., Drumm B. Molecular mimicry of ferret gastric epithelial blood group antigen A by Helicobacter muselae. Gastroenterology. 1998;114:690–696. [PubMed: 9516389]
137.: Odenbreit S., Püls J., Sedlmaier B., Gerland E., Fischer W., Haas R. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science. 2000;287:1497–1500. [PubMed: 10688800]
138.: O'Rourke J. L., Lee A., Fox J. G. Helicobacter infection in animals: a clue to the role of adhesion in the pathogenesis of gastroduodenal disease. Eur. J. Gastroenterol. Hepatol. 1992;4(Suppl. 1):S31–S37.
139.: O'Rourke J. L., Lee A., Fox J. G. An ultrastructural study of Helicobacter mustelae and evidence of a specific association with gastric mucosa. J. Med. Microbiol. 1992;36:420–427. [PubMed: 1613782]
140.: Otto G., Fox J. G., Wu P.-Y., Taylor N. S. Eradication of Helicobacter mustelae from the ferret stomach: an animal model of Helicobacter (Campylobacter) pylori chemotherapy. Antimicrob. Agents Chemother. 1990;34:1232–1236. [PMC free article: PMC171790] [PubMed: 2393285]
141.: Pagliaccia C., De Bernard M., Lupetti P., Ji X., Burroni D., Cover T. L., Papini E., Rappuoli R., Telford J. L., Reyrat J.-M. The m2 form of the Helicobacter pylori cytotoxin has cell type-specific vacuolating activity. Proc. Natl. Acad. Sci. USA. 1998;95:10212–10217. [PMC free article: PMC21487] [PubMed: 9707626]
142.: Parsonnet J. Helicobacter pylori in the stomach—a paradox unmasked. N. Engl. J. Med. 1996;335:278–280. [PubMed: 8657247]
143.: Parsonnet J., Hansen S., Rodriguez L., Gelb A. B., Warnke R. A., Jellum E., Orentreich N., Vogelman J. H., Friedman G. D. Helicobacter pylori infection and gastric lymphoma. N. Engl. J. Med. 1994;330:1267–1271. [PubMed: 8145781]
144.: Parsonnet J., Vandersteen D., Goates J., Sibey R. K., Pritikin J., Chang Y. Helicobacter pylori infection in intestinal and diffuse-type gastric adenocarcinomas. J. Natl. Cancer Inst. 1991;83:640–643. [PubMed: 2023282]
145.: Paster B. J., Lee A., Dewhirst F. E., Fox J. G., Tordoff L. A., Fraser G. J., O'Rourke J. L., Taylor N. S., Ferrero R. The phylogeny of Helicobacter felis sp. nov., Helicobacter mustelae, and related bacteria. Int. J. Syst. Bacteriol. 1991;41:31–38. [PubMed: 1704791]
146.: Peek R. M. J., Miller G. G., Tham K. T., Perez-Perez G. I., Zhao X., Atherton J. C., Blaser M. J. Heightened inflammatory response and cytokine expression in vivo to cagA⁺ Helicobacter pylori strains. Lab. Invest. 1995;71:760–770. [PubMed: 8558837]
147.: Poltorak A., He X., Smirnove I., Liu M.-Y., Van Huffel C., Du X., Birdwell D., Alejos E., Silva M., Galanos C., Freudenberg M., Ricciardi-Castagnoli P., Layton B., Beutler B. Defective LPS signalling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282:2085–2088. [PubMed: 9851930]
148.: Qureshi S. T., Larivière L., Leveque G., Clermont S., Moore K. J., Gros P., Malo D. Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J. Exp. Med. 1999;189:615–625. [PMC free article: PMC2192941] [PubMed: 9989976]
149.: Radin J. M., Eaton K. A., Krakowka S., Lee A., Otto G., Fox J. G. Helicobacter pylori infection in gnotobiotic beagle dogs. Infect. Immun. 1990;58:2606–2612. [PMC free article: PMC258862] [PubMed: 2370111]
150.: Rasko D. A., Wilson T. J. M., Zopf D., Taylor D. E. Lewis antigen expression and stability in Helicobacter pylori isolated from serial gastric biopsies. J. Infect. Dis. 2000;181:1089–1095. [PubMed: 10720535]
151.: Reed K. D., Berridge B. R. Campylobacter-like organisms in the gastric mucosa of rhesus monkeys. Lab. Anim. Sci. 1988;38:329–331. [PubMed: 3411925]
152.: Romaniuk P. J., Zoltowska B., Trust T. J., Lane D. J., Olsen G. J., Pace N. R., Stahl D. A. Campylobacter pylori, the spiral bacterium associated with human gastritis, is not a true Campylobacter sp. J. Bacteriol. 1987;169:2137–2141. [PMC free article: PMC212113] [PubMed: 3571163]
153.: Roth K. A., Kapadia S. B., Martin S. M., Lorenz R. G. Cellular immune responses are essential for the development of Helicobacter felis-associated gastric pathology. J. Immunol. 1999;163:1490–1497. [PubMed: 10415051]
154.: Rudmann D. G., Eaton K. A., Krakowka S. Ultrastructural study of Helicobacter pylori adherence properties in gnotobiotic piglets. Infect. Immun. 1992;60:2121–2124. [PMC free article: PMC257125] [PubMed: 1563801]
155.: Sakagami T., Dixon M. F., O'Rourke J., Howlett R., Alderuccio F., Vella J., Shimoyama T., Lee A. Atrophic gastric changes in both Helicobacter felis and Helicobacter pylori infected mice are host dependent and separate from antral gastritis. Gut. 1996;39:639–648. [PMC free article: PMC1383385] [PubMed: 9026476]
156.: Sakagami T., Vella J., Dixon M. F., O'Rourke J., Radcliff F., Sutton P., Shimoyama T., Beagley K., Lee A. The endotoxin of Helicobacter pylori is a modulator of host-dependent gastritis. Infect. Immun. 1997;65:3310–3316. [PMC free article: PMC175469] [PubMed: 9234792]
157.: Salomon H. Über das spirillum des Saugetiermagens und sein Verhalten zu den Belegzellen. Zentralbl. Bakteriol. Parasiterkd. Infektionskr. Hyg. 1896;19:433–441.
158.: Satin B., Del Giudice G., Della Bianca V., Dusi S., Laudanna C., Tonello F., Kelleher D., Rappuoli R., Montecucco C., Rossi F. The neutrophil-activating protein (HP-NAP) of Helicobacter pylori is a protective antigen and a major virulence factor. J. Exp. Med. 2000;191:1467–1476. [PMC free article: PMC2213429] [PubMed: 10790422]
159.: Segal E. D., Falkow S., Tompkins L. S. Helicobacter pylori attachment to gastric cells induces cytoskeletal rearrangements and tyrosine phosphorylation of host cell proteins. Proc. Natl. Acad. Sci. USA. 1996;93:1259–1264. [PMC free article: PMC40067] [PubMed: 8577751]
160.: Seymour C., Lewis R. J., Kim M., Gagnon D. F., Fox J. G., Dewhirst F. E., Paster B. J. Isolation of Helicobacter strains from wild bird and swine feces. Appl. Environ. Microbiol. 1994;60:1025–1028. [PMC free article: PMC201428] [PubMed: 8161169]
161.: Sharma S. A., Tummuru M. K. R., Blaser M. J., Kerr L. D. Activation of IL-8 gene expression by Helicobacter pylori is regulated by transcription factor-κB in gastric epithelial cells. J. Immunol. 1998;160:2401–2407. [PubMed: 9498783]
162.: Shen Z., Fox J. G., Dewhirst F. E., Paster B. J., Foltz C. J., Yan L., Shames B., Perry L. Helicobacter rodentium sp. nov., a urease-negative Helicobacter species isolated from laboratory mice. Int. J. Syst. Bacteriol. 1997;47:627–634. [PubMed: 9226892]
163.: Shomer N. H., Dangler C. A., Whary M. T., Fox J. G. Experimental Helicobacter pylori infection induces antral gastritis and gastric mucosa-associated lymphoid tissue in guinea pigs. Infect. Immun. 1998;65:4858–4864. [PMC free article: PMC108246] [PubMed: 9596724]
164.: Skouloubris S., Thiberge J. M., Labigne A., Reuse H. D. The Helicobacter pylori UreI protein is not involved in urease activity but is essential for bacterial survival in vivo. Infect. Immun. 1998;66:4517–4521. [PMC free article: PMC108549] [PubMed: 9712811]
165.: Smythies L. E., Waites K. B., Lindsey J. R., Harris P. R., Ghiara P., Smith P. D. Helicobacter pylori-induced mucosal inflammation is Th1 mediated and exacerbated in IL-4, but not IFN-γ, gene-deficient mice. J. Immunol. 2000;165:1022–1029. [PubMed: 10878379]
166.: Solnick J. V., O'Rourke J., Lee A., Paster B. J., Dewhirst F. E., Tompkins L. S. An uncultured gastric spiral organism is a newly identified Helicobacter in humans. J. Infect. Dis. 1993;168:379–385. [PubMed: 8335974]
167.: Stanley J., Linton D., Burens A. P., Dewhirst F. E., On S. L. W., Porter A., Owen R. J., Costas M. Helicobacter pullorum sp. nov.—genotype and phenotype of a new species isolated from poultry and from human patients with gastroenteritis. Microbiology. 1994;140:3441–3449. [PubMed: 7533595]
168.: Stanley J., Linton D., Burens A. P., Dewhirst F. E., Owen R. J., Porter A., On S. L. W., Costas M. Helicobacter canis sp. nov., a new species from dogs: an integrated study of phenotype and genotype. J. Gen. Microbiol. 1993;139:2495–2504. [PubMed: 8254320]
169.: Steer H. W. Surface morphology of the gastroduodenal mucosa in duodenal ulceration. Gut. 1984;25:1203–1210. [PMC free article: PMC1432316] [PubMed: 6500361]
170.: Stein M., Rappuoli R., Covacci A. Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation. Proc. Natl. Acad. Sci. USA. 2000;97:1263–1268. [PMC free article: PMC15590] [PubMed: 10655519]
171.: Sutton P., Wilson J., Genta R., Torrey D., Savinainen A., Pappo J., Lee A. A genetic basis for atrophy: dominant non-responsiveness and helicobacter induced gastritis in F(1) hybrid mice. Gut. 1999;45:335–340. [PMC free article: PMC1727630] [PubMed: 10446099]
172.: Taylor N. S., Fox J. G., Yan L. In-vitro hepatotoxic factor in Helicobacter hepaticus, H. pylori and other Helicobacter species. J. Med. Microbiol. 1995;42:48–52. [PubMed: 7739025]
173.: Taylor N. S., Hasubski A. T., Fox J. G., Lee A. Haemagglutination profiles of Helicobacter species that cause gastritis in man and animals. J. Med. Microbiol. 1992;37:299–303. [PubMed: 1279175]
174.: Telford J. L., Ghiara P., Dell'Orco M., Comanducci M., Burroni D., Bugnoli M., Tecce M. F., Censini S., Covacci A., Xiang Z., Papini E., Montecucco C., Parente L., Rappuoli R. Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease. J. Exp. Med. 1994;179:1653–1658. [PMC free article: PMC2191472] [PubMed: 8163943]
175.: Ulevitch R. J., Tobias P. S. Recognition of gram-negative bacteria and endotoxin by the innate immune system. Curr. Opin. Immunol. 1999;11:19–22. [PubMed: 10047547]
176.: van Doorn N. E. M., Namavar F., Sparrius M., Stoof J., Rees E. P. v., Doorn L.-J. v., Vandenbroucke-Grauls C. M. J. E. Helicobacter pylori-associated gastritis in mice is host and strain specific. Infect. Immun. 1999;67:3040–3046. [PMC free article: PMC96618] [PubMed: 10338517]
177.: Wang T., Dangler C. A., Chen C., Goldenring J. R., Koh T. J., Raychowdhury R., Coffey R. J., Ito S., Varro A., Fox J. G. Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric carcinoma. Gastroenterology. 2000;118:36–47. [PubMed: 10611152]
178.: Wang T. C., Goldenring J. R., Ito S., Dangler C., Mullar A., Jeon W. K., Koh T. J., Fox J. G. Mice lacking secretory phospholipase A2 show altered apoptosis and differentiation with Helicobacter felis infection. Gastroenterology. 1998;114:675–689. [PubMed: 9516388]
179.: Ward J. M., Anver M. R., Haines D. C., Benveniste R. E. Chronic active hepatitis in mice caused by Helicobacter hepaticus. Am. J. Pathol. 1994;145:959–968. [PMC free article: PMC1887338] [PubMed: 7943185]
180.: Ward J. M., Fox J. G., Anver M. R., Haines D. C., George C. V., Collins M. J., Gorelick P. L., Nagashima K., Gonda M. A., Gilden R. V., Tully J. G., Russell R. J., Benveniste R. E., Paster B. J., Dewhirst F. E., Donovan J. C., Anderson L. M., Rice J. M. Chronic active hepatitis and associated liver tumors in mice caused by a persistent bacterial infection with a novel Helicobacter species. J. Natl. Cancer Inst. 1994;86:1222–1227. [PubMed: 8040890]
181.: Watanabe T., Tada M., Nagai H., Sasaki S., Nakao M. Helicobacter pylori infection induces gastric cancer in Mongolian gerbils. Gastroenterology. 1998;115:642–648. [PubMed: 9721161]
182.: Wegmann W., Aschwanden M., Schaub N., Aenishanslin W., Gyr K. Gastritis associated with Gastrospirillum hominis—a zoonosis? Schweiz Med. Wochenschr. 1991;121:245–254. [PubMed: 2011719]
183.: Whary M. T., Morgan T. J., Dangler C. A., Gaudes K. J., Taylor N. S., Fox J. G. Chronic active hepatitis induced by Helicobacter hepaticus in the A/JCr mouse is associated with a Th1 cell-mediated immune response. Infect. Immun. 1998;66:3142–3148. [PMC free article: PMC108325] [PubMed: 9632578]
184.: Wirth H.-P., Yang M., Dubois A., Berg D. E., Blaser M. J. Host Lewis phenotype-dependent selection of H. pylori Lewis expression in rhesus monkeys. Gut. 1998;43:A26. [PMC free article: PMC2579782] [PubMed: 16720729]
185.: Wirth H.-P., Yang M., Peek R. M. J., Tham K. T., Blaser M. J. Helicobacter pylori Lewis expression is related to the host Lewis phenotype. Gastroenterology. 1997;113:1091–1098. [PubMed: 9322503]
186.: Wotherspoon A. C., Doglioni C., Diss T. C., Pan L., Moschini A., de Boni M., Isaacson P. G. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet. 1993;342:575–577. [PubMed: 8102719]
187.: Yamaoka Y., Kita M., Kodama T., Sawai N., Kashima K., Imanishi J. Induction of various cytokines and development of severe mucosal inflammation by cagA gene positive Helicobacter pylori strains. Gut. 1997;41:442–451. [PMC free article: PMC1891528] [PubMed: 9391240]
188.: Yamaoka Y., Kwon D. H., Graham D. Y. A M_r 34,000 proinflammatory outer membrane protein (oipA) of Helicobacter pylori. Proc. Natl. Acad. Sci. USA. 2000;97:7533–7538. [PMC free article: PMC16580] [PubMed: 10852959]
189.: Yokota K., Kurebayashi Y., Takayama Y., Hayashi S., Isogai H., Isogai E., Imai K., Yabana T., Yachi A., Oguma K. Colonization of Helicobacter pylori in the gastric mucosa of Mongolian gerbils. Microbiol. Immunol. 1991;35:475–480. [PubMed: 1921762]
190.: Young V. B., Chien C.-C., Knox K. A., Taylor N. S., Schauer D. B., Fox J. G. Cytolethal distending toxin in avian and human isolates of Helicobacter pullorum. J. Infect. Dis. 2000;182:620–623. [PubMed: 10915100]
191.: Young V. B., Knox K. A., Schauer D. B. Cytolethal distending toxin sequence and activity in the enterohepatic pathogen Helicobacter hepaticus. Infect. Immun. 2000;68:184–191. [PMC free article: PMC97119] [PubMed: 10603386]
192.: Zevering Y., Jacob L., Meyer T. F. Naturally acquired human immune responses against Helicobacter pylori and implications for vaccine development. Gut. 1999;45:465–474. [PMC free article: PMC1727643] [PubMed: 10446121]

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