Key host–pathogen interactions fordesigning novel interventions againstHelicobacter pyloriAlison L. Every

Centre for Animal Biotechnology, School of Veterinary Science, The University of Melbourne, Parkville, Victoria, 3010, Australia

Review

Helicobacter pylori can persist in the stomach of infectedindividuals for life, in the face of chronic inflammationand low pH. Efforts to develop vaccines have largelyfailed and, in the wake of emerging antibiotic resistance,novel therapeutic approaches must be considered. Thisreview will discuss recent salient findings of host factorsthat modulate inflammatory responses to H. pylori withthe aim of harnessing this knowledge for developingnovel therapeutics. In addition, new approaches to vac-cine development will be reviewed. Ultimately, the de-velopment of efficacious therapeutic interventions willlikely need to consider host–pathogen interactions toenhance host immunity and circumvent bacterial eva-sion strategies.

Helicobacter pylori infectionHelicobacter pylori is a Gram-negative bacterium whichhas exquisitely adapted to survive in the acidic, hostileenvironment of the stomach. H. pylori is extremely motileand is found in the mucus layer lining the stomach. Bypenetrating this thick mucus layer, the bacteria can attachto gastric epithelial cells, thus avoiding being ‘washed’through the stomach. H. pylori infection tends to persistfor the life of the host and, with more than half thepopulation of the world being infected, it is not surprisingthat H. pylori strains have co-evolved with Homo sapiens[1]. For this reason, and due to several cunning adapta-tions, the bacteria are able to induce low-level inflamma-tion to gain access to the nutrients required for them togrow and survive, but simultaneously evade host immuneresponses. Importantly, H. pylori is presently the onlybacterial species classified as a type 1 carcinogen by theWorld Health Organization (WHO) [2] and remains asignificant cause of morbidity and mortality worldwide.Approximately one in five infected individuals developdisease, including either peptic ulcer disease, gastric mu-cosal-associated lymphoid tissue lymphoma and, in theworst case (approximately 1–2% of infected individuals),gastric adenocarcinoma. Gastric cancer remains the sec-ond leading cause of death from malignancy worldwide [3]and, with H. pylori being a major cause, it is clear that H.pylori infection still has a major impact on the global

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� 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tim.2013.02.007

Corresponding author: Every, A.L. (aevery@unimelb.edu.au)Keywords: Helicobacter pylori; mucin; adjuvant; antioxidant; vaccine; stomach pH.

disease burden. Clearly there is a need to develop noveltherapies and, ideally, a highly efficacious vaccine, basedon a sound understanding of H. pylori and its interplaywith the human host. This review will summarize recentfindings in the context of host–pathogen interactions andmodulation of inflammation as well as highlighting recentadvances in vaccine development.

H. pylori virulence factors and diseaseThe development and progression of disease following H.pylori infection is influenced by bacterial and host factors. Amyriad of H. pylori virulence factors are known to shape theinflammatory response in the host. Perhaps the best-stud-ied are those encoded by the cytotoxin-associated genespathogenicity island (cagPAI). Containing up to 32 genes[4], strains expressing cagPAI are more virulent and arestrongly associated with development of severe disease [5].These genes include those encoding the type IV secretionsystem, which effectively injects CagA [6] and other effectormolecules, such as peptidoglycan [7], into host epithelialcells. Phosphorylation of CagA inside the cell triggers acascade of events which result in cell motility, elongation,proliferation, and inflammation (reviewed in [8]). Many ofthe processes involving the cagPAI gene products have beenwell-described. Recently, a comprehensive genetic analysisof 38 representative isolates from various geographicregions revealed the strong conservation of the geneticcontent and gene arrangement of cagPAI [9]. However, thisstudy also highlighted the multiple cagPAI proteins towhich no function has been assigned. An improved under-standing of the function of the cagPAI components, whichhave such a strong impact on disease outcome, is essentialfor identification of novel therapeutic targets. To this end,CagL, a component of the type IV secretion system thatmediates binding to gastric epithelial cells [10], was recentlyfound to induce interleukin (IL)-8 production independentlyof CagA translocation or nucleotide-binding oligomerizationdomain 1 (NOD1) signaling [11]. This valuable information,particularly when considered in concert with the function ofother cagPAI components, will be essential for developingnew drugs, which will likely be more efficacious if they targetmultiple proteins or processes. Moreover, these drug targetshave the added advantage of reducing the inflammatoryresponse to H. pylori. It would therefore be prudent toinclude one or more cagPAI components as drug targetswhen designing novel vaccines or therapies.

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Another major virulence factor, vacuolating cytotoxin(VacA), induces cytoplasmic vacuolation and can triggerprocesses resulting in apoptosis, inflammation, and modu-lation of T cell function [8]. Other molecules expressed byH. pylori, including the outer inflammatory protein A,duodenal ulcer promoting gene A, urease, and lipopolysac-charide, have known associations with the pathogenesisand severity of disease. Undoubtedly, bacterial virulencefactors play a central role in determining the outcome ofinfection. The contribution of these bacterial virulencefactors has been reviewed extensively elsewhere[8,12,13] and is therefore not covered in depth here.

Host factorsAlthough approximately half of the world human popula-tion is infected with H. pylori, less than 20% of people willever develop overt clinical symptoms, and this can beexplained partly by varying degrees of virulence amongstrains and geographical regions [8,12,13]. Environmentalfactors, such as diet, smoking, and salt intake, can alsosignificantly impact on disease outcome. It is becomingincreasingly recognized that a multitude of host geneticfactors determine whether a person remains asymptomaticor develops gastric disease. This review provides a succinctaccount of host factors that influence susceptibility tosevere outcomes of H. pylori infection. Host genetic factorsencoding cytokines or pattern-recognition receptors, suchas Toll-like receptors that contribute to the severity of H.pylori disease outcome have been reviewed extensivelyelsewhere [14,15]. Other host factors that impact uponH. pylori disease severity include MUC1 and its role inthe inflammatory response as well as sex-specific variationin stomach pH that determines the spatial distribution ofH. pylori.

MUC1

Mucins are high molecular weight glycoproteins, adornedwith a complex array of O-linked oligosaccharides, whichbind to a broad range of microbial molecules [16]. The mostextensively studied membrane-associated mucin is MUC1,which is a major constituent of the glycocalyx in thegastrointestinal mucosa and estimated to be up to500 nm in length, suggesting that it will tower above othermolecules in the glycocalyx [17]. MUC1 is also expressed byhematopoietic cells, including monocytes, plasma cells,activated T cells, and dendritic cells [18–21]. Constantinternalization of MUC1 by clathrin-mediated endocytosisfollowed by recycling back to the cell surface facilitatescarriage of cargo into the cell [22]. For a long time MUC1was thought purely to have a barrier function, but itssignaling capabilities have recently been investigated[23–25]. The cytoplasmic domains (CD) of cell-surfacemucins are complex, contain phosphorylation motifs, andare highly conserved across species, consistent with impor-tant intracellular functions. Phosphorylation of the MUC1-CD and molecular interaction with b-catenin links MUC1to the Wnt pathway, which is involved in cell growth,migration, and wound repair [24,26–30].

Two studies in humans have reported a link betweenpolymorphisms in the lengths of variable numbers oftandem repeats (VNTR) within the MUC1 gene and

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the development of gastritis [31] and gastric cancer[32]. A more recent study has demonstrated strong link-age disequilibrium with two single-nucleotide polymor-phisms (SNPs) affecting MUC1 promoter activity thatwas associated with diffuse-type gastric cancer [33].Muc1 was shown to play a central role in limiting bothH. pylori colonization and associated inflammation inMuc1-deficient mice [34] (Figure 1B). Interestingly,Muc1 deficiency did not impact on the colonization levelsor inflammation induced by the closely related Helico-bacter felis [35]. This likely reflects the different mecha-nisms by which these species interact with the gastricepithelium. Indeed, H. felis, unlike H. pylori, is thoughtnot to adhere directly to the gastric epithelium in vivo[36–38]. Importantly, the substantial difference in theimpact of Muc1 on the development of inflammationbetween H. pylori and H. felis infection reflects theimportance of how a direct interaction between H. pyloriand Muc1 can limit the inflammatory response. Thedifference in Muc1 binding and, hence, the ability ofMuc1 to limit inflammation between H. pylori and H.felis infection presents an exciting avenue for investigat-ing how Muc1, through direct interaction with bacteria,can limit inflammation, with H. felis being a good controlthat induces inflammation that is not regulated by Muc1.

Indeed, Muc1 limits colonization of the gastric mucosa[39]. As the most highly expressed mucin in the stomachand, in view of its long filamentous nature, it was postu-lated that steric hindrance could account for the ability ofMuc1 to limit H. pylori colonization. Indeed, H. pyloriexhibited increased binding to a gastric cancer cell line(MKN7) with reduced MUC1 expression [39]. Importantly,however, H. pylori also bind directly to MKN7-derivedMUC1, which is mediated by the bacterial adhesins BabAand SabA (Figure 1B). MUC1 also acted as a releasabledecoy, whereby shedding the a subunit of MUC1 wasinitiated by H. pylori-binding in a BabA- and SabA-depen-dent manner, thus facilitating clearance of H. pylori [39].Knockdown studies indicated that cleavage was, in part,mediated by matrix metalloproteinase-14. Furthermore,the ability of MUC1 to protect gastric epithelial cells fromapoptosis was demonstrated. The next major challenge isto determine how MUC1 contributes to curtailing theinflammatory response to H. pylori and what role, ifany, expression of MUC1 on hematopoietic cells has onthe progression of disease.

Stomach pH

One of the most important features of H. pylori is its abilityto survive and persist within the highly acidic environmentof the stomach. Several adaptations have facilitated thisability to withstand the assault of low pH (as low as 1.4 inthe lumen). One is its hypermotility to ensure that thebacteria swim through the mucus, such that they canadhere to the gastric epithelium, and therefore resideand persist in an area where the pH is closer to neutral[38]. H. pylori also synthesizes vast quantities of urease,which hydrolyses urea, resulting in the production ofammonia and bicarbonate, and this adaptation is requiredfor its persistence in the highly acidic gastric lumen [40,41](Figure 1A,F).

An�oxidants: vaccine targets

TRENDS in Microbiology

pH in male mice Increased coloniza�on Decreased inflamma�on

MF

Inflamma�on

Neutrophil

Stomach lumen Key:

T cell ac�va�on in Peyer’s patches

and LNs

T cell

DC

T cell

DC

DC-an�gen transport to draining LNs

T cell migra�on

O2.–

O2.–

Cytokines

Cytokines Cytokines

T cell

DC

Epithelial cell

O2.–

O2.–O2

.– O2.–

O2.–

O2.–O2

.–

H2O

H2O

H2O O2

O2H2O

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H2O O2

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Adhesins Urease

An�-oxidants

Mucin

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H. pylori an�gen

(A)

(B)(E)

(F)

(D)

(C)(D)

Figure 1. Key host–pathogen interactions that affect Helicobacter pylori colonization and disease. (A) Reduced acidity in the stomach lumen of male mice results in

increased colonization by H. pylori across the length of the stomach, with a concomitant inhibition of the inflammatory response [42]. In comparison, female mice have

lower luminal pH with lower bacterial colonization, but more severe gastritis [42]. (B) H. pylori adhesins, BabA and SabA, mediate binding to Muc1, which limits

colonization by acting as a releasable decoy [39] and concomitantly limits gastritis [34]. (C) H. pylori antigen is sampled by dendritic cells (DCs) in the stomach, which traffic

to mesenteric lymph nodes (LNs) and activated T cells [73]. M cells in Peyer’s patches also sample antigen, which is subsequently transported to underlying dendritic cells,

which activate T cells [74]. Targeting M cells in Peyer’s patches represents a novel approach to improve immune responses to H. pylori vaccines [67]. (D) Epithelial cells,

macrophages (MF), and activated T cells produce cytokines and chemokines that recruit neutrophils and more macrophages, resulting in acute gastritis.

Immunomodulatory compounds or adjuvants that improve immune through manipulation of the cytokine and chemokine response represent attractive therapeutic

targets. (E) Neutrophils, which can migrate across the epithelium [75], and macrophages produce reactive oxygen species (ROS) such as superoxide (O2�–) molecules to

attack H. pylori. (F) H. pylori express numerous factors to help them evade immunity including poorly immunogenic lipopolysaccharide (LPS) as well as urease, which

facilitates persistence in the extreme acidity of the stomach lumen. Antioxidants (e.g., superoxide dismutase) also protect from oxidative attack by quickly and efficiently

dismutating ROS (e.g., O2�–). Antioxidants therefore represent attractive vaccine targets because they are essential for colonization, and this approach may also help

enhance immunity to H. pylori [50,51,58]. More efficacious vaccines may be developed by targeting multiple bacterial components.

Review Trends in Microbiology May 2013, Vol. 21, No. 5

In addition, H. pylori predominantly resides in theantrum and cardia of the murine stomach, whereas inthe corpus there are relatively few bacteria [42]. Indeed,Lee et al. [43] first hypothesized in 1995 that the absence ofbacteria from the corpus likely reflects the increased acidi-ty in this region. Moreover, hypochlorhydria is a major riskfor gastric cancer development, and patients with corpusgastritis are more likely to develop this disease [44].

Recently, perturbations in gastric pH were shown toimpact on the severity of H. pylori-associated gastritis [42](Figure 1A). In female 129/Sv mice, the majority of bacteriawere found in the antrum as well as the antrum/corpus andcorpus/limiting ridge transitional zones. However, H. py-lori was present in male mice along the entire length of thestomach, including the corpus. Moreover, male mice exhib-ited significantly increased gastric pH. Most importantly,male mice developed significantly less gastritis after 2weeks and up to 6 months of infection. Although sex-specific differences in gastric pH have not been reportedin humans, such differences indicate that the reduced

gastric acidity permits H. pylori to colonize the entirestomach, enabling them to suppress gastritis [42]. Thislikely occurs via a number of mechanisms, including thesuppression of T cell responses, via g-glutamyl transpep-tidase production [45]. Importantly, these data emphasizethe relevance of considering other physiological factors topredict likely disease outcome. Although it is difficult toperform this type of analysis in humans, these interestingobservations warrant further investigation. Moreover,when designing novel diagnostic tests and therapeuticsit is also important to consider how the outcome of infectionmay be influenced by gender.

Anti-H. pylori vaccinationCurrently, H. pylori infection is treated with a combinationof a proton pump inhibitor (e.g., omeprazole) and theantibiotics clarithromycin and amoxicillin. However, suc-cessful treatment of H. pylori infection remains low, with35–85% of infections being cleared, reaching lowest valuesin some European countries [46]. The gradual but steady

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emergence of antibiotic-resistant strains represents a ma-jor obstacle in the treatment of H. pylori infection [46].Reinfection also remains problematic. New approachesneed to be considered for treatment of this disease. Dis-tressingly, in some cases the initial diagnosis of H. pyloriinfection comes too late, when carcinoma is already estab-lished; in these instances prognosis is usually poor. In lightof the potentially horrific consequences of a failure toeradicate an H. pylori infection, alternative therapies mustbe developed. Ideally, the best way to reduce the impact ofH. pylori-associated disease on a global scale will be todevelop a safe and efficacious vaccine. Although the questto develop such a vaccine has proved fruitless to date [47],vaccination is likely to be the best strategy for dealing withan infection of this scale and socioeconomic importance.

Antioxidant enzymes as vaccine antigens

For the development of a safe and effective vaccine, it isimportant to equip ourselves with an arsenal of novelvaccine candidates. Of all the vaccine candidates testedin humans to date, not one has elicited significant protec-tion [47]. Even so, the reduced bacterial burdens observedin many mouse trials and in some human trials [48,49]provide a tantalizing hint that sterilizing immunity mayindeed be obtainable. Perhaps one means to attain thisgoal would be to establish a prioritized panel of antigensthat can enhance a protective immune response and resultin the elimination of infection. Recently, H. pylori super-oxide dismutase (HpSOD) and thiolperoxidase (Hptpx)were demonstrated to be additional antigens capable ofinducing immunity and reducing H. pylori burdens whencodelivered with an appropriate adjuvant [50,51]. Indeed,HpSOD and Hptpx represent attractive vaccine candi-dates for two major reasons – they are expressed on thesurface of the bacteria [52–54], therefore increasing accessto the antigen by the immune system, and they are alsoessential for H. pylori survival in vivo [55,56] – where theyprotect against reactive oxygen species produced boththrough internal metabolic processes and by neutrophilsand macrophages (Figure 1E,F). Studies that have inves-tigated the importance of specific antioxidants for coloni-zation, or as vaccine candidates, are summarized inTable 1. However, surface-expressed antioxidants may

Table 1. Helicobacter pylori antioxidants as vaccine targets

Enzyme Colonization by mutant Ref

Catalase (KatA) Reduced after long-term

infection

[75]

Superoxide dismutase (SOD) Greatly impaired (<5%

of mice colonized)

[54]

Thiolperoxidase (Tpx) Greatly impaired (<5%

of mice colonized)

[55]

Alkyl hydroperoxide reductase (AhpC) Unable to colonize [55]

aAbbreviations: CT, cholera toxin; o.g., orogastric gavage; i.n., intranasal; IMX, ISCOM

b#, decrease; ", increase.

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also reduce inflammation locally and may thus impactupon host immune responses. By limiting HpSOD and/or Hptpx function, this two-pronged approach might resultin the induction of protective immune responses whileconcomitantly preventing the immune-dampening actionsof bacterial antioxidant enzymes. Indeed, the entire anti-oxidant system of H. pylori represents an attractive set ofvaccine target molecules for precisely these reasons –enhanced anti-H. pylori immunity and disinhibition ofhost inflammatory and hence immune responses. Thishypothesis is further supported by the finding that theH. pylori antioxidants catalase [51,57] and alkylhydroper-oxide reductase [58] are also protective vaccine antigens.The H. pylori antioxidant system comprising these andother enzymes described above was the subject of ourrecent review [59]. Targeting enzyme pathways such asthese may lead to development of novel treatments thatcould enhance the ability of the host to clear infection.

Targeting M cells in Peyer’s patches

In considering past failures it is worth recognizing that H.pylori vaccines tested in humans have elicited significanthumoral [48,60–62] or cellular immune responses [49], orboth [63,64]. Unfortunately, this has yet to translate tosignificant protection, and there are no reports of steriliz-ing immunity. The role regulatory T cells play in reducingvaccine efficacy is also being increasingly recognized [47].Novel adjuvants or immunomodulators may represent thebest means of circumventing this immunoregulation andmay facilitate the induction of sterilizing immunity. Forexample, vaccine antigen can be directly targeted toPeyer’s patches, which are lymphoid nodules located with-in the lamina propria of the ileum (Figure 1C). It is herethat specialized microfold or M cells facilitate antigen-sampling and transfer to antigen-presenting cells in theunderlying mucosa. One approach along these lines hasinvolved using the lectin, Ulex europaeus agglutinin 1(UEA-1), which binds Fuca1,2-terminal saccharidesexpressed by M cells within the murine gastrointestinaltract, to agglutinate the SS1 strain of H. pylori [65–67].Interestingly, when formalin-fixed H. pylori SS1 aggluti-nated with UEA-1 was delivered orally, a significant re-duction in bacterial colonization levels was observed

Protective vaccine formulationa Protective outcomeb Ref

KatA + CT, o.g. # Colonization, " IgA and IgG [56]

KatA + CT, i.n. # Colonization, " IgA and IgG [50]

KatA + IMX, s.c. # Colonization, " IgG [50]

Virus-like particles encoding

KatA epitopes, s.c.

# Colonization, " IgG2a [76]

SOD + CT, o.g. # Colonization, " IgG [49]

SOD + IMX, s.c. # Colonization, " IgG [49]

SOD + CT, i.n. # Colonization, " IgG

(no IgA)

[50]

Tpx + IMX, s.c. # Colonization, " IgG [50]

Tpx + CT, i.n. # Colonization, " IgG [50]

AhpC + alum, s.c. # Colonization, " IgG [57]

and AhpC + CT, o.g. # Colonization, " IgG [57]

ATRIX; s.c., subcutaneous.

Review Trends in Microbiology May 2013, Vol. 21, No. 5

following challenge compared with unvaccinated mice and,most importantly, compared with mice vaccinated withunagglutinated but formalin-fixed H. pylori. These micealso displayed significantly higher antibody responsesthan did mice vaccinated with formalin-fixed H. pylorialone [67]. This study emphasizes the importance of har-nessing knowledge of host factors, and particularly thosethat affect host immunity, for improving the effectivenessof vaccines.

Adjuvants

Numerous formulations of various adjuvants have beentested in clinical trials for identification of optimal H.pylori vaccines. Generally, the inclusion of an adjuvantis required to elicit robust, protective immunity in mice.The exception appears to be subcutaneous vaccinationwith whole, formalin-fixed H. pylori, which does effect areduction in bacterial load [67,68]. However, on the whole,the adjuvants of choice in mice have been cholera toxin(CT) and heat-labile toxin (LT) of Escherichia coli. Asmucosal adjuvants, CT and LT have proven highly effica-cious for generating strong mucosal immune responsesand, hence, protective immunity [69]. However, in humansCT and LT both induce watery diarrhea; indeed no mucosaladjuvant has been approved for human use in a vaccine.ISCOMATRIXTM, which is safe for use in humans, hasbeen shown to induce protective immunity in mice whenused boost the immune responses to either whole celllysate, formalin-inactivated bacteria [68,70], H. pyloriadhesin A [68], or superoxide dismutase [50]. Althoughyet to be tested fully for use as a mucosal adjuvant inhumans, these studies suggest that further investigation isrequired to assess the efficacy and safety of ISCOMA-TRIXTM for H. pylori vaccination in humans. However,despite the advances in achieving vaccine-induced protec-tion in mice, substantial work is required to assess adju-vants for use in humans. Clearly the lack of a safe andeffective mucosal adjuvant has hampered efforts to developa H. pylori vaccine. Therefore, it is imperative not only toidentify and characterize appropriate vaccine antigens, butalso to strive to develop novel, safe, and effective adjuvants,particularly those that may boost mucosal immunity.

Concluding remarks: novel, integrated approach forrational drug design and vaccine developmentAlthough a safe and effective H. pylori vaccine has not yetbeen developed for use in humans, there have beenglimpses of success in rodents and humans [47,71], indi-cating promise. For the design of a safe and efficaciousvaccine, many factors need to be considered; these relate tobacterial factors and the role of host immune responses.

First, by identifying essential processes and/or enzymesas vaccine targets we can increase the likelihood that animmune response generated against said antigens willresult in significant impairment in bacterial function,which will in turn increase the chances of eliciting steriliz-ing immunity. It is likely that this approach will require amulti-component vaccine that will ensure multiple anti-gens are targeted from a single process or pathway. OnePhase I clinical trial conducted by Novartis, which tested amulticomponent vaccine comprising VacA, CagA, and

neutrophil-activating protein adjuvanted with alum (in-tramuscular delivery), demonstrated induction of antigen-specific memory T cells [63]. Gastroenterologists and Heli-cobacter researchers alike eagerly await the outcomes offurther Phase I/II clinical trials. Importantly, early suc-cesses with multicomponent vaccines suggest that withcareful selection of antigens that target a single but criticalpathway or process, such as the H. pylori antioxidantsystem, we can potentially inhibit that pathway and im-pair or even kill the bacteria.

Other important factors relating to vaccine and/or drugdesign are host immune and inflammatory responses. Inconsidering this it is important to note that, despite induc-ing a strong T helper (Th1) and Th17 immune response, H.pylori infection persists for life, and therefore sophisticatedstrategies must be employed for design of safe and effica-cious vaccines. In addition, vaccination against H. pyloriinfection induces transient post-immunization gastritis[72], which would be an undesirable side-effect in humans.An ideal H. pylori vaccine will induce a strong T cellresponse without concomitant induction of severe gastritis.To this end our approach may require the development ofnew adjuvants that can induce sterilizing immunity butthat also possess immunomodulatory functions that cansimultaneously reduce inflammation. This will requireincreased knowledge of factors that trigger the inflamma-tory cascade in the host. Specifically, it will be important tocontinue to enhance our understanding of the complexhost–pathogen interactions that occur during H. pyloriinfection, such as the integral role that MUC1 plays inminimizing H. pylori-associated inflammation. Converselyit is important to consider how proinflammatory moleculesproduced by H. pylori itself, such as CagL [11], can induceinflammation. This knowledge can be harnessed for ratio-nal drug and/or vaccine design. Moreover, targeting H.pylori systems, such as the antioxidant system, representsan ideal means of inducing robust, protective immunity.

However, it seems likely that the best approach for thedevelopment of novel treatments and/or vaccines will in-corporate knowledge of chemokines, cytokines, or otherproinflammatory molecules that enhance protective immu-nity (Figure 1D). Indeed, the most efficacious therapy mayalso target or inactivate proinflammatory mediators thatsubsequently amplify inflammation without concomitantinduction of protective immunity. By utilizing newly dis-covered factors that modulate H. pylori inflammation andimmunity, as described in this review, we will be in a betterposition to tailor a vaccine or treatment that can inducelong-lasting protection without inducing unacceptableimmunopathology.

AcknowledgmentsI gratefully acknowledge Prof Jean-Pierre Scheerlinck for his help withpreparation of the figure and I thank Prof Robin Gasser for providingcomments on the manuscript.

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