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

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Helicobacter pylori: Physiology and Genetics.

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Chapter 46In Vivo Adaptation to the Host

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1 and 2.

1 Unité de Pathogénie Bactérienne des Muqueuses, Institut Pasteur, 28 rue du Docteur Roux, Paris, 75724, France
2 Institute of Infections and Immunity, University of Nottingham, Nottingham, NG7 2UH, United Kingdom

Members of the genus Helicobacter colonize the gastric or intestinal mucosae of mammals. Among the species that have adapted to colonize the gastric mucosa, several (including Helicobacter pylori and Helicobacter mustelae) naturally infect a very narrow range of animal hosts (48). Indeed, H. pylori, which is highly adapted to human gastric mucosa, is rarely associated with natural infections in other animal hosts. Nevertheless, experimental H. pylori infections have been described in a variety of large and small mammals, including gnotobiotic piglets, mice, and gerbils (3, 22, 23, 25, 30, 49, 80).

The specificity of H. pylori for the human host is the consequence of a series of adaptations that probably occurred many thousands of years ago (17). This adaptation has provided H. pylori with an important advantage in vivo because unlike most gastrointestinal pathogens, it has little competition from other bacteria in its preferred ecological niche. Survival of pathogens is dependent on their ability to disseminate and infect new hosts (46). One consequence of the high degree of host adaptation of H. pylori is that it cannot survive for long periods outside the body. Transmission of H. pylori therefore requires close contact between individuals, and if H. pylori is to establish an infection in another host it needs to be able to adapt rapidly to the challenges of its new environment. The aptitude of H. pylori strains for ongoing adaptation to its host is reflected by the extremely high degree of genetic diversity within the species (31, 41, 44, 60). This has given rise to a population of closely related genetic variants, also known as a quasi-species (17, 31, 33, 47).

Genetic diversity in H. pylori appears to be generated primarily by horizontal gene transfer as a result of DNA recombination via natural transformation or possibly conjugation (1, 45, 70), and by the facilitated acquisition of mutations due to the absence of DNA repair/modification systems common to other bacteria (5). Interstrain diversity in H. pylori is a manifestation of the influence of selective pressures on the bacterium in vivo and occurs at both the population (macrodiversity) and single host (microdiversity) level. The selective pressures to which invading H. pylori bacteria would be exposed include those exerted by the environment (e.g., exposure to antibiotics and changes in gastric pH or mucosal defenses) and host factors (e.g., specific and nonspecific defense mechanisms). Macrodiversity, which is reflected by the clustering of H. pylori strains with related genotypes among individuals of specific ethnic origins (60, 74), is the product of changes that have occurred over very long periods of time and is linked to human evolution. In contrast, microdiversity is associated with temporal changes that occur in H. pylori during more defined periods, such as that within an infected host. It is likely that the relationship between colonizing H. pylori bacteria and the host is a dynamic and interactive one in which the bacteria are constantly responding to changes in the host, and vice versa. H. pylori has evolved several mechanisms that enable it to vary gene expression (4, 64, 71) and that are critical for host adaptation. While the importance of macrodiversity in H. pylori evolution is well founded, the role of strain adaptation in bacterial survival in vivo and in transmission to uninfected hosts is only beginning to be appreciated.

Although clinical studies provide the most accurate means of studying H. pylori adaptation to the host, such studies suffer from obvious limitations. The availability of small animal models of H. pylori infection has permitted an improved understanding of H. pylori adaptation to the host. These models provide a unique opportunity to investigate precise questions relating to bacterial adaptation in vivo, under controlled experimental conditions. Major caveats to this, however, are that these models depend on the use of H. pylori strains that have been adapted to "unnatural" hosts and do not entirely duplicate the conditions present within the human stomach. For these reasons, models using nonhuman primates appear to be particularly well suited for investigations on H. pylori-host interactions.

In Vitro versus In Vivo

Much of our current understanding of H. pylori pathogenesis has been derived from in vitro studies. Nevertheless, in vitro methods cannot reproduce the complex interactions between pathogen and host. An important aspect of such interactions that is absent from in vitro assays is the host's immune response. Until recently, the contribution of host factors to pathogenesis was generally disregarded in most definitions of microbial pathogenicity (14).

The findings from studies of bacterial pathogenesis in H. pylori have underscored the differences between in vitro and in vivo conditions; these showed that knockout mutants, which grew normally in culture media, were affected in their abilities to colonize animal hosts. Several of these mutants were defective in certain well-established virulence properties such as motility, while others contained mutations in the genes encoding proteins with primarily metabolic or physiological functions (16, 54, 67). Metabolic functions are thus likely to play an important role in H. pylori colonization of, and adaptation to, the host. This observation would be consistent with the findings from in vivo-based investigations of bacterial virulence in other pathogens.

The capacity of H. pylori strains to colonize different human and nonhuman animal hosts is both bacterial strain and host dependent (Table 1). Experimental infection studies in which nonhuman primates became colonized with a predominant strain after administration of pools of H. pylori strains provided direct evidence of in vivo strain selection in the host (22, 23). Although various H. pylori strains have been reported to colonize animals, few colonized to the high bacterial loads seen in infected humans (7) (Table 1). The bacterial factors that allow certain H. pylori strains to adapt more readily to animal hosts than others have yet to be identified. One study reported that H. pylori strains with an increased aptitude to colonize animal hosts all possessed a spiral morphology (32), while others stressed the importance of an active form of motility, as shown by the degree of colony spreading on soft agar plates or by the transcription levels of the major flagellin gene of H. pylori (flaA) (25, 51).

Table 1. Colonization of animal hosts by H. pylori isolates.

Table 1

Colonization of animal hosts by H. pylori isolates.

In vivo passage has been shown to result in increased infectivity in gastric Helicobacter spp., and several workers have reported increased infectivity in H. pylori strains after passage in large mammals (piglets and monkeys) (3, 51) and mice (49), respectively. These findings are consistent with the concept of host adaptation by H. pylori. H. pylori strains that had been passaged in mice displayed differences in the synthesis of several proteins (120, 180, and 260 kDa), and it was proposed that these changes may contribute to the adaptation of the strains to the host (35). In contrast to the findings above, Wirth et al. (80) reported that an in vitro attenuated variant of a gerbil-adapted strain (G1.1) could not easily regain its capacity to colonize that host after in vivo passage in mice. This observation highlights that colonization is a complex interplay between host as well as bacterial factors.

In common with other pathogenic bacteria, H. pylori loses its capacity to colonize animals following multiple subcultures in vitro (62, 80). Indeed, initial attempts to establish H. pylori infections in mice were unsuccessful because of the use of laboratory-adapted strains for the preparation of challenge inocula (13). Indeed, the gerbil-adapted G1.1 strain rapidly lost its ability to colonize after in vitro passage, with no colonization evident after 20 subcultures (80). In the mouse-adapted H. pylori SS1 strain, however, reduced infectivity for mice occurred only after >100 subcultures in vitro (62). The extent to which repetitive in vitro culture reduces the infectivity of H. pylori in animals, again, appears to be bacterial strain and host dependent.

The basis for decreased infectivity in in vitro-adapted H. pylori isolates is poorly understood. Several authors described changes in the phenotypes of H. pylori isolates having undergone either repeated subcultures in vitro or growth under different culture conditions. Repeated subculture of H. pylori resulted in various changes, including loss of lipopolysaccharide (LPS) O side chains (58) and of catalase activity (52). Nevertheless, animal-adapted H. pylori isolates that had been passaged repeatedly in vitro did not exhibit differences in the LPS-associated Lewis antigen phenotype (80) or in the production of major cellular proteins (62). In addition, the use of random amplified polymorphic DNA analysis, a very sensitive fingerprinting technique for detecting rearrangements or point mutations in bacteria, did not reveal any major modifications in DNA arrangement of isolates following multiple passages in vitro (62, 80).

Various studies have also been unable to show significant differences at the DNA level in H. pylori isolates after long-term colonization (20, 49). The apparent genomic stability of these isolates contrasts with the very high level of genetic diversity seen among randomly selected H. pylori strains. This discrepancy may be explained by the fact that the studies were performed with H. pylori strains that had already been adapted to laboratory and in vivo conditions, respectively. Therefore, differences in DNA arrangement might only be detectable during the transition phase of strain passage from in vitro to in vivo environments, or during colonization of an uninfected host.

Mechanisms of Adaptation to the Host

Recombination

Analysis of the diversity in certain alleles among H. pylori strains from diverse geographic origins has shown that H. pylori displays a relatively high frequency of recombination when compared to other bacteria (1, 70). In H. pylori, the frequency of mixing of alleles at different loci is sufficiently high as to disrupt clonal groupings, and thus the bacterium exhibits a panmictic population structure (70). Certain H. pylori strains are naturally competent and can take up foreign DNA in vitro by transformation and conjugation. Although it has been observed that horizontal DNA transfer events between pathogenic bacteria can be facilitated by the presence of factors found only in the host environment (55, 65), the frequency of in vivo transfer of H. pylori DNA appears to be lower than that occurring in vitro (20, 24, 45).

Evidence of genetic exchange in vivo between H. pylori strains during chronic infection has been provided by the work of Kersulyte and colleagues (45). These workers demonstrated the emergence in vivo of recombinant alleles as a result of recombination between the genes encoding certain putative outer membrane proteins in two H. pylori strains. By characterizing the strains for the presence of the cytotoxin-associated gene (cag) pathogenicity island (cag PAI), which is believed to encode bacterial virulence factors (15, 17), it was shown that the dominant H. pylori strain in this individual converted from a cag PAI+ to a cag PAI genotype (45). This change in genotype occurred through the acquisition of genetic material from the cag PAI strain, rather than by loss of the PAI.

It has been proposed that specific genes or gene fragments are associated with different degrees of recombination. Consistent with this, genome sequencing has revealed the presence on the H. pylori genome of several areas known as plasticity zones, in which a high degree of genetic heterogeneity was found between strains, and which contained a significantly different (G+C)% than the remainder of the genome (4). The cag PAI was identified as being one such region, and this is consistent with the relatively high occurrence of deletions or DNA rearrangements in this region in vivo (1, 39). In addition, the presence in H. pylori of multiple copies of certain genes (paralogs) within the chromosome suggests that intrastrain recombination is at least theoretically feasible (4, 71).

Recombination represents a major molecular mechanism for genetic variability in H. pylori over long periods of time and may be involved in the generation of clonal groupings (1, 70). It is also possible that recombination plays a role in the selection of more highly adapted variants during the initial phases of in vivo colonization. However, the rarity of major allelic variations in H. pylori strains recovered from members within families (73), as well as in strains recovered after long-term follow-up (>7 years) of the same individuals (47), suggests that inter- or intrastrain recombination occurs infrequently during established infections. Although there have been reports of multiple H. pylori infections in humans (42), most individuals seem to be infected with one predominant H. pylori strain (34, 57). Similarly, it was shown that the inoculation of simian (22, 23) and murine (20) hosts with multiple H. pylori strains did not give rise to hybrid strains, but rather to the selection of predominant colonizing strains.

Gene Regulation

As might be expected from such a highly host-adapted bacterium, H. pylori has a comparatively small genome (1.6 Mb) (4, 71). Although genome sequencing has revealed a relative paucity of global regulatory proteins and two-component regulatory systems, H. pylori possesses certain regulatory proteins that allow the bacterium to sense and respond to environmental changes. These include the global ferric uptake regulator (Fur), the transcriptional activator, FlgR, and the autoregulatory transcriptional repressor, HspR (4, 68, 69, 71). In addition, sigma factor promoter elements, such as those for σ28, σ54, and σ80, have been identified upstream of certain virulence genes in H. pylori (4, 71, 76), but the environmental stimuli to which these promoters are responsive have not been clarified. Recently, it was shown that H. pylori gene expression could be regulated posttranscriptionally by mRNA decay in response to environmental pH (2).

In common with other mucosal pathogens (e.g., Haemophilus influenzae and Neisseria spp.), H. pylori has been proposed to use slipped-strand mispairing as a basis for antigenic variation and adaptive evolution (4, 5, 71). This mechanism involves modifications in the lengths of dinucleotide or homopolymeric repeats located in the 5′ regions of genes. Numerous series of such repeats have been identified on the H. pylori genome and were most often present within open reading frames encoding putative cell envelope proteins or proteins involved in either unknown or DNA restriction/modification functions (4, 5, 64, 71). Slipped-strand mispairing-dependent regulation of the genes encoding fucosyltransferases, which are responsible for the Lewis antigen phenotype of H. pylori LPS O antigen, has become a paradigm for gene regulation in the organism (6, 63, 79, 82).

Finally, the fact that numerous type II methyl-transferase-encoding genes have been identified on the H. pylori genome, and that the corresponding enzymes appear to lack identifiable restriction-subunit partners, has been taken to suggest that DNA methylation might be important for H. pylori gene regulation (5).

Mutation

Mutations at the single nucleotide level appear to represent another possible mechanism for change in H. pylori bacteria during adaptation to the host. This is facilitated by the absence in H. pylori of certain DNA mismatch repair systems, such as the homologs of MutL or MutH (5). An example of how point mutations might lead to phenotypic changes in H. pylori, and thus allow the organism to adapt to the in vivo conditions, is best illustrated by the development of antibiotic resistance in the bacterium (37, 53, 78) (see below). There are other examples, however, in which single nucleotide differences between H. pylori strains were either not associated with amino acid base substitutions (e.g., glmM) (44) or otherwise resulted in amino acid modifications with unknown effects on the biological functions of the proteins (e.g., hspA) (60). The benefits of such modifications for H. pylori are currently unclear but might reflect the potential of H. pylori to develop mutations that become dominant through strong selective pressures such as increasing concentrations of antibiotic in the local environment.

Selection in the Host

Bacterial Factors

The adaptation to the host of H. pylori is reflected in regulatory, metabolic, and physiological features of the bacterium. The mucous layer covering the epithelium of the human stomach is the preferred niche of H. pylori bacteria. The high acidity (pH of 1 to 2) within the gastric lumen, combined with the high viscosity and reduced oxygen tension of the mucous layer, is selective for Helicobacter spp. (48). H. pylori interacts intimately with the gastric epithelium and yet remains distant from the neutrophils and mononuclear cells present in inflamed gastric tissue. In addition, H. pylori has evolved an LPS of low biological activity that reduces the likelihood of severe inflammation and thus promotes long-term colonization of the host (59).

The severity of H. pylori-induced inflammation is influenced by the presence in H. pylori strains of the cag PAI, which is responsible for the synthesis of the proinflammatory cytokine interleukin-8 (IL-8) by gastric epithelial cells (15). It was reported that H. pylori variants that no longer harbored the cag PAI had a selective advantage in vivo (45), suggesting that modulation of host immune responses may be an important factor in H. pylori adaptation to the host. Similarly, colonization studies in mice demonstrated that an H. pylori mutant that had spontaneously lost the capacity to induce IL-8 synthesis in gastric epithelial cells was better able to colonize mice than was the parent strain that retained this property (75) (Table 1). Crabtree and colleagues (19) also showed that H. pylori has the ability to down-regulate cag PAI-dependent inflammation via the production of a cag PAI-encoded protein with homology to the VirD4 protein of the plant pathogen Agrobacterium tumefaciens.

As discussed earlier, it has been suggested that slipped-strand repair-regulated synthesis of surface proteins represents an important mechanism for H. pylori adaptation to the host. Various authors have described slipped-strand repair-dependent phase variation in Lewis antigen expression (Lex and Ley) among different H. pylori variants; however, the biological significance of this process for in vivo adaptation has not been definitively established (6, 79). While two studies (in humans and primates) found that the relative proportions of Lex and Ley expression in H. pylori isolates mimicked those of the host (81, 82), another human study did not find such a correlation (63). Moreover, investigations using transgenic mice expressing the Lewis B (Leb) human blood group antigen were unable to show a change in Lewis antigen expression in the infecting host strain (32).

Evidence of metabolic adaptation in H. pylori has recently arisen from molecular studies on the biological role of arginase (RocF), a key enzyme in H. pylori nitrogen metabolism (54). Arginase-negative H. pylori mutants, which were generated by allelic exchange using two types of inactivation procedures, were found to have significantly lower activities of serine dehydratase, an enzyme involved in ammonia generation. This effect on serine dehydratase was independent of the H. pylori strain background and of the type of gene inactivation procedure used. In addition, although both types of H. pylori RocF mutants tested were sensitive to acid killing in vitro, only one of these demonstrated a significantly reduced level of colonization in the H. pylori SS1 model. It was, therefore, suggested that pleomorphic effects had occurred in vitro as a result of the inactivation of rocF, and it is plausible that additional mutation(s) were generated in vivo to compensate for the defect in arginase production in mutant clones (54). So-called "second site compensatory mutations" leading to increased fitness in vivo have also been reported in Salmonella enterica serovar Typhimurium strains passaged in mice (10).

Differences in colonization efficiency of other metabolically affected H. pylori mutants have been reported in studies on the γ-glutamyltranspeptidase (GGT) of H. pylori (11, 16). In one of these studies, GGT H. pylori mutants were unable to colonize Swiss outbred mice (16), whereas in another report GGT H. pylori mutants were unaffected in their abilities to colonize C57BL/6 inbred animals (11). These contradictory findings may be explained by the different genetic backgrounds of the host, and it seems likely that a degree of metabolic function lost in these mutants could have been compensated for in vivo. In support of this suggestion is a preliminary report describing the isolation of urease-negative H. pylori variants from the gastric biopsies of infected individuals (72). As H. pylori urease plays an essential role in host colonization, this finding represents a potentially very strong argument for the existence of metabolic redundancy in H. pylori and its role in the organism's adaptation to the host. For such a conclusion to be made, it will be necessary to further characterize these urease-negative variants.

The autochthonous microbiota may also influence adaptation by H. pylori. Although commensal bacteria do not generally occupy the same niche as H. pylori, it is plausible that the metabolic products of these bacteria have an effect on H. pylori growth and survival. The ability to compete with other bacteria would be particularly important when changes in the gastric environment associated with long-term H. pylori colonization, such as hypochlorhydria and gastric atrophy, might lead to overgrowth by commensal bacteria. Lactobacillus spp., which may be found in the normal fasting human stomach (43) and which also permanently colonize the stratified squamous epithelium of the murine stomach, have been shown to inhibit the growth of H. pylori in vitro (9, 56). Moreover, certain Lactobacillus spp. of the autochthonous microbiota of mice also suppressed H. pylori multiplication in vivo (43). The production of an antibacterial peptide might be one means by which H. pylori has adapted to the presence of competitive microorganisms in the stomach (61). However, whether this peptide is effective against a broad range of microorganisms, including gram-positive bacteria, is not currently known.

Environmental Factors

Changes in gastric acid production, as well as exposure of the host to antibiotics, can have a profound effect on H. pylori colonization. Deregulation of acid production in the human stomach may occur as a direct result of colonization by H. pylori or by the administration of acid-suppressive therapies, such as proton pump inhibitors. Omeprazole-mediated suppression of acid production results in a redistribution of H. pylori bacteria from a predominantly antral location to a more dense colonization in the fundus (50). Similar findings have been reported from work in the Helicobacter felis mouse model (21). It appears that H. pylori, which is a facultatively acid-tolerant neutrophile, is able to adapt to variations in local acid production in the stomach by altering its niche so as to ensure optimum survival and growth. These changes in the localization of H. pylori in the stomach can have an important impact on the pattern and distribution of gastritis and in the development of duodenal and gastric ulcers (77).

Exposure of H. pylori-infected individuals to antibiotics for the treatment of unrelated infections results in the development of antimicrobial resistance in H. pylori in vivo. It was recently shown in the H. pylori SS1 mouse model that exposure of H. pylori-infected mice to metronidazole resulted in the selection of mixed metronidazole-sensitive and -resistant populations within the murine stomach (38). Moreover, repeated exposure of animals to the antibiotic increased the ratio of metronidazole-resistant to -sensitive isolates. The majority of the metronidazole-resistant isolates recovered from the mice contained one or more frameshift or missense mutations in the rdxA gene, which encodes a nitroreductase responsible for the reductive activation of metronidazole by H. pylori (37). These findings demonstrate that H. pylori is able to adapt to the presence of antimicrobial agents in the local environment, although whether the development of resistance enhances virulence is unlikely. Indeed, the acquisition of antibiotic resistance by bacteria generally confers the cost of reduced survival in an antibiotic-free environment (10). Consistent with this, in vitro growth studies with metronidazole-sensitive and -resistant isolates found that the latter were less able to thrive under stationary-phase conditions (40). Despite this, recent work in the S. enterica serovar Typhimurium mouse model has shown that antibiotic-resistant bacteria were still able to colonize mice. Furthermore, the authors were able to restore virulence in antibiotic-resistant bacteria by in vivo passage without concomitant loss of resistance. The increased fitness displayed by these strains was attributed to the accumulation of various types of compensatory mutations. The implication of this work is that the accumulation of second site mutations might give resistant bacteria a selective advantage over sensitive ones, even in an antibiotic-free environment. It is, therefore, possible that RdxA H. pylori mutants recovered from the host might also acquire secondary mutations associated with greater levels of fitness.

Clarithromycin resistance in H. pylori is predominantly associated with A to G transition mutations in the 23S rRNA gene and rarely associated with A to C mutations (78). In contrast, A to T mutations have never been reported. Recently, a biological basis for this selection was provided by studies in which the in vitro growth properties of different clarithromycin-resistant strains, which had been generated by site-specific mutagenesis, were compared. The A to G mutants had a growth advantage over the other mutants, implying that this particular substitution does not impair ribosomal function in protein synthesis (78).

Data from clinical studies have shown that mixed clarithromycin-sensitive and -resistant H. pylori isolates occurred in hosts with no reported history of macrolide exposure (53). Although the clarithromycin-resistant bacteria represented an extremely small proportion of the total H. pylori population in these individuals, it was suggested that resistant clones may become dominant after exposure to clarithromycin. Under such circumstances, A to G clarithromycin-resistant mutants would be expected to have a selective advantage over other mutants. It is currently unclear whether clarithromycin-resistant H. pylori strains can truly arise spontaneously in vivo, and what the benefits of this phenotype might be for the organism.

Host Factors

Individuals with H. pylori infection develop vigorous humoral and cellular immune responses to the bacterium. These responses are characterized by the recruitment and activation of inflammatory cells via the effects of proinflammatory cytokines, such as IL-8, tumor necrosis factor-α, IL-6, and interferon-γ. In addition, innate response mechanisms such as iron sequestration, nutrient limitation, and the synthesis of bacteriostatic factors (e.g., nitric oxide and lysozyme) probably play a role in host defense. By mathematical modeling, Blaser and Kirschner showed that the host response is a key parameter leading to either transient or persistent infection (12). Host responses in the model were defined as including innate and adaptive immunity, as well as the other nonspecific mechanisms cited above. The model also stated that while there is probably a "universal" response to infection that is unable to suppress colonization by H. pylori, other factors, including the particular bacterial strain or the state of the host at the time of exposure, can lead to clearance of the pathogen. Although the concept of spontaneous elimination of H. pylori infection by the host is not widely accepted, there is direct experimental evidence of this from primate studies (22, 23). Also, studies in B- and T-cell-deficient SCID mice have shown that adaptive immune responses were able to partially suppress gastric H. pylori colonization in that host (22, 23).

In most instances, however, host immune responses do not result in elimination of the bacterium. Thus, for H. pylori to establish a chronic infection, an equilibrium needs to be established between the pathogen and the host. Modulation of host immune responses is one means by which bacterial adaptation might be achieved. There are data from both human and mouse studies demonstrating the capacity of H. pylori to down-regulate host immune responses (28, 66). In mice, this down-regulation was accompanied by reduced T-helper 1 cytokine-dependent cell-mediated responses, and increased T-helper-2-dependent humoral responses (66).

Host susceptibility or resistance to H. pylori infection is another important consideration in bacterial adaptation to the host. In nonhuman primates, it was observed that animals differed in their susceptibilities to different H. pylori strains during the initial phase of infection (22, 23). Furthermore, long-term colonization by specific H. pylori strains was dependent on host factors. Although there has been one report concerning the influence of human leukocyte antigens in host resistance or susceptibility to H. pylori infection, no significant correlation could be found (83). In contrast, a recent study of individuals from families with a history of gastric cancer demonstrated that polymorphisms in the IL-1β gene cluster were associated with hypochlorhydria and an increased risk of gastric cancer (27). The polymorphisms described were proposed to enhance production of IL-1β, which is an important proinflammatory cytokine and a powerful inhibitor of gastric acid secretion. It is, therefore, reasonable to assume that similar links will be made between genes related to immune functions, and the occurrence of host resistance or susceptibility to H. pylori infection, as has been described for other bacterial infections (8).

Conclusions and Perspectives

Colonization of the human gastric mucosa by H. pylori occurs as a result of a dynamic interactive process between the pathogen and its host. While many of the bacterial mechanisms involved in this adaptation are beginning to be elucidated, little is known of the changes that occur in the host during the initiation and establishment of infection by H. pylori. The availability of the human genome sequence and cDNA array/differential display technologies permitting the simultaneous analysis of the expression of thousands of host genes in response to an infection (18), as well as the development of novel transgenic and knockout mouse models, should allow a better understanding of the contribution of host factors to microbial pathogenesis.

Acknowledgment

Peter J. Jenks is supported by a Research Training Fellowship in Medical Microbiology from the Wellcome Trust (Ref. 044330).

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