Abstract
Helicobacter pylori infection is commonly acquired during childhood, can persist lifelong if not treated, and can cause different gastric pathologies, including chronic gastritis, peptic ulcer disease, and eventually gastric cancer. H. pylori has developed a number of strategies in order to cope with the hostile conditions found in the human stomach as well as successful mechanisms to evade the strong innate and adaptive immune responses elicited upon infection. Thus, by manipulating innate immune receptors and related signaling pathways, inducing tolerogenic dendritic cells and inhibiting effector T cell responses, H. pylori ensures low recognition by the host immune system as well as its persistence in the gastric epithelium. Bacterial virulence factors such as cytotoxin-associated gene A, vacuolating cytotoxin A, or gamma-glutamyltranspeptidase have been extensively studied in the context of bacterial immune escape and persistence. Further, the bacterium possesses other factors that contribute to immune evasion. In this chapter, we discuss in detail the main evasion and persistence strategies evolved by the bacterium as well as the specific bacterial virulence factors involved.
Access provided by CONRICYT-eBooks. Download chapter PDF
Similar content being viewed by others
Keywords
1 Introduction
Despite of eliciting a strong immune response, H. pylori can persist lifelong in the gastric mucosa of infected individuals. H. pylori infection leads to gastric inflammation, which in most of the cases is asymptomatic, but can progress to a more severe pathology and even gastric cancer (Wroblewski et al. 2010). Therefore, H. pylori is considered as class I carcinogen by the World Health Organization (IARC 1994). To survive in the hostile conditions found in the stomach and escape the host’s immune response, H. pylori has developed different sophisticated strategies, which depend on the presence of certain bacterial virulence factors. Thus, to establish colonization, urease activity as well as flagella are important, while once established in its niche, other virulence factors encoded by the cytotoxin-associated gene A (CagA), vacuolating cytotoxin A (VacA), or gamma-glutamyltranspeptidase (GGT) become decisive to shape the host’s immune response in order to favor bacterial persistence. These virulence factors can directly alter cellular processes and signaling cascades of host cells or induce changes in the cellular milieu, which also culminate in altered immune cell responses.
Different cell types are involved in the complex immune response toward H. pylori, which the bacterium is able to manipulate in order to escape and persist. Thus, epithelial cells and innate immune cells, which constitute the first line of defense against H. pylori, are profoundly altered by the bacterium, leading to an ineffective clearance of the pathogen. These changes are decisive to shape the subsequent adaptive immune response, mainly mediated by effector T cells, whose function is also compromised, and contribute to bacterial persistence.
In this chapter, we discuss in detail different strategies employed by H. pylori to escape from the host’s immune response and persist in the stomach, paying special attention to the bacterial virulence factors involved.
2 Innate Immune Evasion Strategies of H. pylori
In order to ensure its persistence, H. pylori manipulates the host’s innate immune response (Fig. 1), which is mainly driven by gastric epithelial cells as well as gastric-resident innate immune cells or innate immune cells recruited upon infection, including dendritic cells (DCs), monocytes/macrophages, and neutrophils.
2.1 Evasion and Manipulation of Pattern Recognition Receptors
Epithelial cells and innate immune cells recognize pathogen-associated molecular patterns (PAMPs) by different immune receptors or pattern recognition receptors (PRRs) expressed at specific subcellular compartments. Upon their activation, PRRs induce diverse downstream signaling pathways important for the clearance of pathogens. H. pylori has developed a number of strategies to avoid detection by Toll-like receptors (TLRs) and to manipulate and suppress TLR—as well as C-type lectin receptor (CLR)-mediated signaling. By this, clearance of the bacterium is impaired and persistent colonization of the human stomach is consolidated.
2.1.1 Evasion of TLR Recognition and Manipulation of TLR-Mediated Signaling
TLRs on gastric epithelial cells and immune cells recognize diverse H. pylori PAMPs such as lipopolysaccharide (LPS) (TLR2 and TLR4), flagellin (TLR5), and bacterial nucleic acids (TLR8 and TLR9). However, by modulating the expression and structure of surface molecules such as LPS or flagellin, H. pylori successfully avoids or dampens recognition by these TLRs (Pachathundikandi et al. 2011, 2015).
LPS is a glycolipid commonly found on the outer membrane of Gram-negative bacteria and composes of three well-defined units: (1) a hydrophobic moiety, lipid A, responsible for the toxic effects; (2) a core oligosaccharide, which contributes to the outer membrane integrity together with lipid A; and (3) the O-antigen, which is a polymer composed of repeating oligosaccharides connected to the core and in direct contact with the extracellular milieu (Whitfield and Trent 2014). By structural modifications in the lipid A and expression and variation of Lewis (Le) antigens terminally exposed on the O-antigen, H. pylori has achieved reduced detection by the immune system. H. pylori lipid A shows lower biological activity than lipid A of other Gram-negative bacteria (Muotiala et al. 1992; Moran and Aspinall 1998). Uncommon phosphorylation and acylation of lipid A are not only responsible for the reduced endotoxicity of H. pylori LPS (Ljungh et al. 1996), but also for its reduced immunogenicity (Moran 2001). Exchange of the 1-phosphate group for a phosphorylethanolamine and removal of the 4′-phosphate group in the H. pylori lipid A backbone increase resistance to antimicrobial peptides and reduce recognition by TLRs (Tran et al. 2006; Cullen et al. 2011). These modifications are extremely important for the successful colonization of the gastric mucosa, since H. pylori mutants deficient for the phosphatases involved in dephosphorylation of lipid A are not able to colonize mice (Cullen et al. 2011).
The O-antigen of H. pylori LPS also contributes to the evasion of bacteria recognition by innate immune cells. The common backbone of this polysaccharide is modified by fucosyltransferases that generate structures mimicking human Lewis antigens and related blood group antigens (Rubin and Trent 2013). Thus, the O-antigen can evade TLR detection since it is not recognized as a foreign molecule but rather as a “self”-antigen. H. pylori can adapt to the host by phase variation of its LPS, in which Le antigens of the bacterium evolve to resemble the gastric Le phenotype of the host (Appelmelk and Vandenbroucke-Grauls 2001). Due to the diversity of Lewis antigens expressed in H. pylori LPS, the exact role of these molecules in infection and disease is not completely clear. Lex and Ley antigens are expressed in almost 80–90% of H. pylori strains (Moran 2008). They have been related to bacterial adhesion (Fowler et al. 2006; Heneghan et al. 2000), and more importantly, they contribute to bacterial molecular mimicry to evade immune responses (Appelmelk and Vandenbroucke-Grauls 2001). It is still under discussion which TLR(s) is/are involved in the recognition of H. pylori LPS, since some studies suggest TLR4 as the main sensor (Ishihara et al. 2004; Kawahara et al. 2005), while others support TLR2 as its receptor (Yokota et al. 2007; Smith et al. 2011). Nevertheless, it is clear that the reduced ability of H. pylori LPS to bind and activate its receptors contributes to bacterial escape from innate immune responses.
H. pylori flagellin, which is an important bacterial factor for motility and colonization, eludes recognition by TLR5, avoiding pro-inflammatory transcription factor and nuclear factor-kappa B (NF-κB) activation (Pachathundikandi et al. 2016). This is due to a modification in residues 89–96 of the N-terminal D1 domain of H. pylori flagellin, important for TLR5 recognition (Andersen-Nissen et al. 2005). In addition, FlaA, the primary flagellar structural component, is not released and is much less pro-inflammatory compared to other bacterial flagellins (Gewirtz et al. 2004).
Apart of having developed mechanisms to escape immune recognition, H. pylori has also acquired strategies to actively manipulate TLR-mediated signaling in order to dampen pro-inflammatory responses. For example, activation of TLR2 signaling induces the expression of many anti-inflammatory cytokines via myeloid differentiation primary response gene 88 (MyD88), particularly IL-10 (Rad et al. 2009). In line, infection of Tlr2 −/− mice indicated an important role for TLR2 signaling in H. pylori-induced immune tolerance. Tlr2 −/− mice were colonized at lower levels than wild-type animals and showed more severe inflammation of the gastric mucosa, reflected by higher levels of interferon (IFN)-γ and lower expression of forkhead box P3 (Foxp3), a transcription factor marking regulatory T cells, IL-10, and IL-17 (Sun et al. 2013).
Another mechanism by which H. pylori suppresses gastric inflammation is the activation of TLR9, which was identified as the main intracellular TLR signaling pathway recognizing H. pylori DNA in DCs (Rad et al. 2009). Activation of TLR9 signaling is suggested to have anti-inflammatory effects at early phases of H. pylori infection. Thus, although Tlr9 −/− mice showed similar bacterial colonization, they presented a more severe gastric inflammation, which was characterized by increased neutrophil infiltration and upregulation of the expression of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interferon-γ (IFN-γ) (Otani et al. 2012).
2.1.2 Inhibition of CLR-Mediated Signaling
H. pylori can modulate immune responses by interacting with another type of PRR, the C-type lectin receptors (CLRs). CLRs expressed on DCs recognize and bind carbohydrates such as mannose, fucose, or glucan, commonly expressed on bacterial surfaces. Of those, Dendritic cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN) can bind H. pylori ligands and is involved in the innate immune response to the bacterium. Specifically, H. pylori Lex and Ley antigens can interact with C-type lectin DC-SIGN on dendritic cells to block the development of Th1 cells (Bergman et al. 2004). Further studies confirmed H. pylori LPS binding to recombinant human DC-SIGN and showed that addition of fucose or incubation with monoclonal antibodies against Le antigens abolished this binding (Miszczyk et al. 2012). Notably, the fucose residues of the DC-SIGN ligands of H. pylori interfere with the signaling complex downstream of DC-SIGN, suppressing pro-inflammatory responses, in contrast to other pathogens expressing mannosylated DC-SIGN that activate pro-inflammatory signaling pathways (Gringhuis et al. 2009). More recently, the expression of macrophage inducible C-type lectin (Mincle) was found to be upregulated in H. pylori-infected macrophages. This CLR interacts with Lewis antigens of H. pylori and induces an anti-inflammatory immune response, which would also contribute to bacterial immune escape and persistence in the host (Devi et al. 2015).
2.2 Inhibition of Phagocytosis and Killing by Reactive Oxygen Species and Nitric Oxide
Bacterial phagocytosis is a central host defense mechanism to eliminate invading bacteria. Upon H. pylori infection, different phagocytes such as neutrophils, polymorphonuclear (PMN) lymphocytes, and monocytes are recruited to the gastric mucosa. However, the bacterium successfully inhibits its own uptake by PMNs and monocytes. This antiphagocytic activity depends on different virulence genes, such as virB7 and virB11, and core components of the type IV secretion system (T4SS) (Ramarao et al. 2000a; Ramarao and Meyer 2001) and contributes to bacterial immune escape. Another strategy used by the bacterium to escape phagocytosis involves intrinsic α-glycosylation of cholesterol. Thus, bacteria lacking cholesterol-α-glycosyltransferase HP0421 (Lebrun et al. 2006) were more susceptible to phagocytosis by macrophages and induced a more potent MHC-restricted T cell activation. In addition, HP0421-deficient bacteria were efficiently cleared from the gastric tissue of infected mice (Wunder et al. 2006), indicating that α-glycosylation of cholesterol by H. pylori represents a prerequisite for the bacterium to escape phagocytosis, T cell activation, as well as bacterial clearance in vivo.
On the other hand, once engulfed by macrophages, different strategies allow H. pylori to survive phagocytosis. Cag pathogenicity island (cagPAI)-positive and VacA-positive H. pylori strains were found to delay actin polymerization and phagosome formation in human and murine macrophages. Once formed, phagosomes underwent clustering and fusion-forming megasomes, wherein H. pylori resisted intracellular killing. (Allen et al. 2000). Other strategies to avoid macrophage-mediated bacterial killing include VacA-related arrest of phagosome maturation in association with the retention of tryptophan aspartate-containing protein (Zheng and Jones 2003) and delayed entry and arrest of phosphatidylinositide 3-kinase (PI3 K)-dependent phagosome maturation via synthesis of cholesteryl glucosides (Du et al. 2014).
Survival of H. pylori within polymorphonuclear cells (PMNs) is also achieved by disrupting the NADPH oxidase system, which produces reactive oxygen species (ROS) in response to the bacterium. NADPH oxidase assembly is inefficient in the phagosome, and although PMNs containing H. pylori produce ROS, they do not accumulate inside the phagosomes but are released to the extracellular space (Allen et al. 2005). H. pylori produces catalase and superoxide dismutase, which detoxify ROS and protect the bacterium from the toxic effects of ROS in vitro and in vivo (Spiegelhalder et al. 1993; Odenbreit et al. 1996; Ramarao et al. 2000b; Seyler et al. 2001; Harris et al. 2002, 2003).
Production of nitric oxide by macrophages represents another mechanism to kill bacteria. H. pylori urease induces the activation of inducible nitric oxide synthase (iNOS) (Gobert et al. 2002b); however, at the same time, H. pylori arginase protects the bacterium against NO-mediated killing by competing with host cells iNOS for the common substrate L-arginine. Thus, macrophages infected with H. pylori deficient for arginase efficiently killed the bacterium, whereas H. pylori wild type did not show loss of survival under the same experimental conditions (Gobert et al. 2001). The induction of arginase II (Arg2) represents a further mechanism by which H. pylori escapes the host innate immune response. Upregulation of Arg2 was detected in H. pylori-induced gastritis in humans and mice (Gobert et al. 2002a), and Arg2 activity attenuated H. pylori-stimulated NO production by limiting iNOS protein expression in vitro and in vivo (Lewis et al. 2010). Notably, treatment with an arginase inhibitor led to increased iNOS protein expression and NO production in gastric macrophages of H. pylori-infected mice (Lewis et al. 2010), confirming that restriction of NO production contributes to H. pylori escape from macrophage-mediated killing.
2.3 Inhibition of Antimicrobial Peptides
As part of the innate immune response, epithelial cells generate a number of antimicrobial peptides to protect the gastrointestinal epithelium from invading bacteria. H. pylori was reported to induce the expression of human beta-defensin 2 (hBD2) (Hamanaka et al. 2001; Bajaj-Elliott et al. 2002; Wehkamp et al. 2003), hBD3 (Kawauchi et al. 2006) and the amphipathic α-helical cathelicidin LL37 (Hase et al. 2003), which also exhibits a wide spectrum of antimicrobial activity. However, in more recent research, different studies have demonstrated that H. pylori is able to manipulate the expression of these antimicrobial substances in order to escape and persist in the gastric mucosa. Thus, the expression of hBD3 is rapidly induced via epidermal growth factor receptor (EGFR)-dependent activation of mitogen-activated protein (MAP) kinase and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling at early stages of H. pylori infection. However, during chronic infection, hBD3 is downregulated by H. pylori CagA-mediated activation of tyrosine phosphatase Src homology 2 domain-containing phosphatase 2 (SHP-2), which terminates EGFR activation and downstream signaling, supporting bacterial viability (Bauer et al. 2012). In addition, the H. pylori T4SS downregulates the expression of hBD1 through NF-κB signaling (Patel et al. 2013). Interestingly, when analyzing biopsies from infected patients, the same authors observed that patients showing higher bacterial colonization and inflammation showed lower hBD1 expression, whereas they did not detect differences in hBD2 (Patel et al. 2013). Notably, H. pylori showed resistance to hDB1, while minimal susceptibility to hBD2 was observed for some strains. On the other hand, hBD3 and LL37 efficiently killed H. pylori; however, these two antimicrobial peptides were only marginally detected in the human stomach (Nuding et al. 2013). Therefore, by manipulating defensin expression and developing resistance against these antimicrobial peptides, H. pylori can more efficiently colonize the gastric mucosa.
3 Immune Tolerance Driven by H. pylori Interaction with Dendritic Cells
DCs are highly specialized antigen-presenting cells, key mediators of the innate and adaptive immune response due to their ability to capture and transfer antigens and regulate T cell responses. DCs can enter the gastric epithelium, where they take up H. pylori and its virulence products (Necchi et al. 2009) and as thus shape adaptive immune responses. H. pylori has evolved a number of strategies to manipulate DC maturation and cytokine production, skewing them toward a tolerogenic phenotype and therefore instructing a regulatory T cell response that contributes to bacterial persistence (Fig. 2).
In first reports, H. pylori undefined secreted factors were reported to inhibit the secretion of IL-12 (Kao et al. 2006), while chronic exposure to the bacterium resulted in increased expression of PD-L1, a member of the B7 family implicated in the inhibition of T cell function, and impaired DC function inhibiting Th1 responses (Mitchell et al. 2007).
Further investigations have implicated the virulence factors CagA, VacA, and GGT in H. pylori-induced tolerogenic effects on DCs. In bone marrow-derived dendritic cells (BMDCs), CagA plays an important role in regulating DCs to inhibit CD4+ T cell differentiation toward a Th1 phenotype. Hence, phosphorylation of CagA inside the cells led to the activation of SHP-2, suppressing the activation of serine/threonine protein kinase-1 (TBK-1), the phosphorylation, and nuclear translocation of interferon regulatory factor 3 (IRF-3) and inducing a reduced interferons production by the DCs (Tanaka et al. 2010). In human DCs, once translocated into the cell, CagA induces a DC semi-mature phenotype characterized by low expression of the costimulatory molecule cluster of differentiation (CD86) and the maturation marker CD83 as well as by low expression of the pro-inflammatory cytokine IL-12p70 and increased expression of IL-10, which favors a regulatory T cell response. These changes are orchestrated by the IL-10-dependent activation of signal transducer and activator of transcription factor 3 (STAT3) (Kaebisch et al. 2014).
The H. pylori virulence factors VacA and GGT are also important to skew the DC-mediated T cell response toward the bacterium, favoring the development of a predominant regulatory phenotype. In mice, VacA and GGT are required for gastric colonization and DC tolerization in vivo and contribute to neonatally acquired immune tolerance (Oertli et al. 2013). VacA was shown to inhibit DC maturation via restoration of the critical suppressor of DC maturation E2 promoter-binding factor-1 (E2F1) expression (Kim et al. 2011). In human DCs, H. pylori GGT also induces a tolerogenic phenotype mainly by repressing the expression of IL-6. This effect is due to the enzymatic activity of GGT, which converts glutamine into glutamate. Glutamate activates metabotropic glutamate receptors expressed on DCs, inhibiting cAMP-mediated regulation of IL-6 expression and thus favoring the expansion of regulatory T cells (Kabisch et al. 2016).
Together, DC tolerization induced by different H. pylori virulence determinants has a major impact on the subsequent adaptive immune response to the bacterium, favoring the expansion of regulatory T cells. Indeed, regulatory T cells are massively recruited to the gastric mucosa of H. pylori-infected subjects (Lundgren et al. 2003; Cheng et al. 2012) and contribute to bacterial persistence and chronic infection by suppressing effector immune responses (Lundgren et al. 2003; Arnold et al. 2011).
4 Manipulation and Inhibition of Effector T Cell Responses
The adaptive immune response toward H. pylori is characterized by the recruitment of CD4+ effector T cells, particularly Th1 and Th17 subsets, which are crucial for the control of the infection and at the same time are implicated in the immunopathological changes resulting from the chronic infection (D’Elios et al. 1997; Bamford et al. 1998; Sayi et al. 2009; Shi et al. 2010; Kabir 2011; Serelli-Lee et al. 2012). As mentioned before, DCs are important regulators and play a key role in defining T cell responses to H. pylori. However, in order to persist in the stomach, the bacterium has also developed mechanisms to directly manipulate and inhibit T cells, rendering them hyporesponsive (Fan et al. 1994). In this context, VacA and GGT are the main bacterial virulence determinants impairing effective T cell responses upon infection, although other bacterial factors such as arginase and the cagPAI also contribute to dampen T cell proliferation and function (Fig. 3).
VacA can interact with T cells in the lamina propria and enter activated human T cells by binding to β2 integrin (CD18), which associates with CD11a, forming the heterodimeric transmembrane receptor lymphocyte function-associated antigen 1 (LFA-1) (Sewald et al. 2008). VacA uptake is facilitated as H. pylori exploits the recycling of LFA-1, and this effect depends on serine/threonine phosphorylation of the β2 integrin cytoplasmic tail by protein kinase C (PKC) (Sewald et al. 2011). Once in the cytoplasm, VacA impairs T cell activation as well as proliferation by different mechanisms. VacA interferes with T cell receptor–IL-2 signaling pathway at the level of calcineurin, a Ca2+/calmodulin-dependent phosphatase. By this, VacA inhibits nuclear translocation of the transcription factor NFAT and prevents transactivation of NFAT-regulated genes specific for T cell immune responses (Gebert et al. 2003). Importantly, VacA suppresses IL-2-mediated cell cycle progression and T cell proliferation through its N-terminal hydrophobic region without affecting IL-2-dependent survival. The N-terminal region of VacA is necessary for the formation of anion-selective membrane channels inhibiting clonal expansion of activated T lymphocytes (Sundrud et al. 2004). Proliferation of T cells is also impaired by the reduction of the mitochondrial membrane potential through H. pylori VacA (Boncristiano et al. 2003), while actin rearrangements, as a result of channel-independent activation of intracellular signaling via the MAP kinases MKK3/6 and p38 as well as the Ras-related C3 botulinum toxin substrate Rac-specific nucleotide exchange factor Vav, dampen T cell activation (Ganten et al. 2007).
Another important virulence factor interfering with T cell proliferation and function is GGT. This secreted low molecular weight protein can directly block T cell proliferation by inducing a G1 cell cycle arrest through disruption of rat sarcoma (Ras) signaling pathway (Gerhard et al. 2005; Schmees et al. 2007). More recently, it was shown that H. pylori GGT compromises metabolic reprogramming of T lymphocytes by depriving them from glutamine (Wüstner et al. 2015). The expression of IL-2, CD25, and effector cytokines IFN-γ and IL-17 was reduced in the presence of H. pylori GGT. Moreover, the expression of the transcription factors c-Myc and IRF4 and signaling cascades as mechanistic target of rapamycin (mTOR) important for T cell metabolic reprogramming were altered by GGT, indicating that the enzymatic activity of GGT is sufficient to hinder effector T cell responses toward the bacterium and thus contribute to H. pylori immune evasion (Wüstner et al. 2015).
Depletion of L-arginine availability by H. pylori arginase is another mechanism affecting T cell proliferation. L-arginine is required for T cell activation and function and is depleted by H. pylori arginase to produce urea. This induces decreased proliferation of T cells and reduced expression of the chief signal transduction CD3ζ-chain of the T cell receptor, which is necessary for T cell activation (Zabaleta et al. 2004).
H. pylori cagPAI-positive strains were found to induce apoptosis of T cells through the induction of the Fas ligand (FasL), limiting host immunity (Wang et al. 2001).
In summary, the inhibition of effector T cells in combination with the development of a regulatory-biased adaptive immune response represents a major mechanism by which H. pylori evades the host immune system and persists even though eliciting strong inflammatory responses.
5 Bacterial Plasticity and Immune Evasion
H. pylori is one of the most variable bacterial genus, exhibiting extensive genetic diversity among different strains (Suerbaum 2000). This high level of diversity not only supports adaptation to its host, but at the same time enables Helicobacter to avoid several aspects of the immune response. Adhesion molecules of H. pylori are not only found in different allelic forms (Pride et al. 2001; Oleastro et al. 2010; Nell et al. 2014), but can also be regulated through on/off mechanisms and were shown to be turned off and replaced by other adhesions after successful colonization (Solnick et al. 2004). These adhesins are also regulated through recombination between various genomic loci. Through this regulation, H. pylori avoids immune recognition of important adhesins.
Further, such genomic variability is also observed within a single host (Kraft et al. 2006) and probably reflects adaptation of H. pylori to the individual host, including adaptation to specific immune responses. This is reflected by the high variability observed in immune responses among infected individuals. At the humoral level, hardly any antigen is recognized in all infected subjects. Rather, most antibody responses toward a single antigen are detected in a minority of patients. Few antigens, such as CagA, chaperonin GroEL, or flagellar hook-associated protein FliD, are recognized in over 80% of infected individuals (Cover et al. 1995; Nomura et al. 2002; Khalifeh Gholi et al. 2013; Shiota et al. 2014; Pan et al. 2014; Michel et al. 2014). Although far less data are available regarding antigen-specific cellular responses, the same seems to be true here. This could be interpreted as an early adaptation mechanism of H. pylori, where protective immune responses lead to rapid epitope changes or selection of subspecies not exhibiting the specific epitope. Over the time, substrains are selected which are weakly recognized.
6 Concluding Remarks
Despite of eliciting strong immune responses, H. pylori has, during coevolution with humans, developed a number of strategies to evade the host immune system and persist in the hostile niche that represents the human stomach. Immune evasion and persistence depend on several bacterial virulence factors, which, on the one hand, induce cellular damage and recruitment of immune cells at the site of infection, but, on the other hand, subvert the host’s responses in order to create a tolerogenic environment allowing the bacterium to persist. Understanding how H. pylori manipulates host immune responses is of foremost importance in order to develop novel and successful therapeutic interventions for the treatment of human populations at high risk of gastric cancer development associated with the infection. This knowledge is also of special relevance in the context of vaccine development against H. pylori, since finding adequate antigens to generate vaccine-mediated protection has been extremely challenging so far. Thus, the identification of conserved bacterial proteins well recognized by the host’s immune system and important to establish strong immune responses able to clear the bacterium seems imperative for the development of successful vaccine formulations. On the other side, further knowledge on the intricate relations between host and pathogen will be useful to develop strategies to mimic and induce some of the bacterial beneficial effects found in asymptomatic carriers (e.g., asthma protection) while avoiding the deleterious consequences of the infection.
In summary, H. pylori is one of the most successful human pathogens able to manipulate the cellular milieu and subvert immune responses in order to ensure its persistence. Although several of the strategies used by H. pylori have been identified in the recent years, there are still many lessons to learn from this exceptional bacterium.
References
Allen LA, Schlesinger LS, Kang B (2000) Virulent strains of Helicobacter pylori demonstrate delayed phagocytosis and stimulate homotypic phagosome fusion in macrophages. J Exp Med 191(1):115–128. doi:10.1084/jem.191.1.115
Allen LA, Beecher BR, Lynch JT, Rohner OV, Wittine LM (2005) Helicobacter pylori disrupts NADPH oxidase targeting in human neutrophils to induce extracellular superoxide release. J Immunol 174(6):3658–3667. doi:10.4049/jimmunol.174.6.3658
Andersen-Nissen E, Smith KD, Strobe KL, Barrett SL, Cookson BT, Logan SM, Aderem A (2005) Evasion of Toll-like receptor 5 by flagellated bacteria. Proc Natl Acad Sci USA 102(26):9247–9252. doi:10.1073/pnas.0502040102
Appelmelk BJ, Vandenbroucke-Grauls C (2001) Lipopolysaccharide Lewis antigens. In: Mobley HLT, Mendz GL, Hazell SL (eds) Helicobacter pylori: physiology and genetics. Washington (DC). Chapter 35. ISBN-10: 1-55581-213-9
Arnold IC, Lee JY, Amieva MR, Roers A, Flavell RA, Sparwasser T, Muller A (2011) Tolerance rather than immunity protects from Helicobacter pylori-induced gastric preneoplasia. Gastroenterology 140(1):199–209. doi:10.1053/j.gastro.2010.06.047
Bajaj-Elliott M, Fedeli P, Smith GV, Domizio P, Maher L, Ali RS, Quinn AG, Farthing MJ (2002) Modulation of host antimicrobial peptide (beta-defensins 1 and 2) expression during gastritis. Gut 51(3):356–361. doi:10.1136/gut.51.3.356
Bamford KB, Fan X, Crowe SE, Leary JF, Gourley WK, Luthra GK, Brooks EG, Graham DY, Reyes VE, Ernst PB (1998) Lymphocytes in the human gastric mucosa during Helicobacter pylori have a T helper cell 1 phenotype. Gastroenterology 114(3):482–492. doi:10.1016/S0016-5085(98)70531-1
Bauer B, Pang E, Holland C, Kessler M, Bartfeld S, Meyer TF (2012) The Helicobacter pylori virulence effector CagA abrogates human beta-defensin 3 expression via inactivation of EGFR signaling. Cell Host Microbe 11(6):576–586. doi:10.1016/j.chom.2012.04.013
Bergman MP, Engering A, Smits HH, van Vliet SJ, van Bodegraven AA, Wirth H-P, Kapsenberg ML, Vandenbroucke-Grauls CMJE, van Kooyk Y, Appelmelk BJ (2004) Helicobacter pylori modulates the T helper cell 1/T helper cell 2 balance through phase-variable interaction between lipopolysaccharide and DC-SIGN. J Exp Med 200(8):979–990. doi:10.1084/jem.20041061
Boncristiano M, Paccani SR, Barone S, Ulivieri C, Patrussi L, Ilver D, Amedei A, D’Elios MM, Telford JL, Baldari CT (2003) The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms. J Exp Med 198(12):1887–1897. doi:10.1084/jem.20030621
Cheng HH, Tseng GY, Yang HB, Wang HJ, Lin HJ, Wang WC (2012) Increased numbers of Foxp3-positive regulatory T cells in gastritis, peptic ulcer and gastric adenocarcinoma. World J Gastroenterol WJG 18(1):34–43. doi:10.3748/wjg.v18.i1.34
Cover TL, Glupczynski Y, Lage AP, Burette A, Tummuru MK, Perez-Perez GI, Blaser MJ (1995) Serologic detection of infection with cagA+ Helicobacter pylori strains. J Clin Microbiol 33(6):1496–1500 (0095-1137/95/$04.00)
Cullen TW, Giles DK, Wolf LN, Ecobichon C, Boneca IG, Trent MS (2011) Helicobacter pylori versus the host: remodeling of the bacterial outer membrane is required for survival in the gastric mucosa. PLoS Pathog 7(12):e1002454. doi:10.1371/journal.ppat.1002454
D’Elios MM, Manghetti M, De Carli M, Costa F, Baldari CT, Burroni D, Telford JL, Romagnani S, Del Prete G (1997) T helper 1 effector cells specific for Helicobacter pylori in the gastric antrum of patients with peptic ulcer disease. J Immunol 158(2):962–967
Devi S, Rajakumara E, Ahmed N (2015) Induction of Mincle by Helicobacter pylori and consequent anti-inflammatory signaling denote a bacterial survival strategy. Sci Rep 5:15049. doi:10.1038/srep15049
Du SY, Wang HJ, Cheng HH, Chen SD, Wang LH, Wang WC (2014) Cholesterol glycosylation by Helicobacter pylori delays internalization and arrests phagosome maturation in macrophages. J Microbiol Immunol Infect (Wei mian yu gan ran za zhi). doi:10.1016/j.jmii.2014.05.011
Fan XJ, Chua A, Shahi CN, McDevitt J, Keeling PW, Kelleher D (1994) Gastric T lymphocyte responses to Helicobacter pylori in patients with H. pylori colonisation. Gut 35(10):1379–1384. doi:10.1136/gut.35.10.1379
Fowler M, Thomas RJ, Atherton J, Roberts IS, High NJ (2006) Galectin-3 binds to Helicobacter pylori O-antigen: it is upregulated and rapidly secreted by gastric epithelial cells in response to H. pylori adhesion. Cell Microbiol 8(1):44–54. doi:10.1111/j.1462-5822.2005.00599.x
Ganten TM, Aravena E, Sykora J, Koschny R, Mohr J, Rudi J, Stremmel W, Walczak H (2007) Helicobacter pylori-induced apoptosis in T cells is mediated by the mitochondrial pathway independent of death receptors. Eur J Clin Invest 37(2):117–125. doi:10.1111/j.1365-2362.2007.01761.x
Gebert B, Fischer W, Weiss E, Hoffmann R, Haas R (2003) Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science 301(5636):1099–1102. doi:10.1126/science.1086871
Gerhard M, Schmees C, Voland P, Endres N, Sander M, Reindl W, Rad R, Oelsner M, Decker T, Mempel M, Hengst L, Prinz C (2005) A secreted low-molecular-weight protein from Helicobacter pylori induces cell-cycle arrest of T cells. Gastroenterology 128(5):1327–1339. doi:10.1053/j.gastro.2005.03.018
Gewirtz AT, Yu Y, Krishna US, Israel DA, Lyons SL, Peek RM (2004) Helicobacter pylori flagellin evades toll-like receptor 5-mediated innate immunity. J Infect Dis 189(10):1914–1920. doi:10.1086/386289
Gobert AP, McGee DJ, Akhtar M, Mendz GL, Newton JC, Cheng Y, Mobley HL, Wilson KT (2001) Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: a strategy for bacterial survival. Proc Natl Acad Sci USA 98(24):13844–13849. doi:10.1073/pnas.241443798
Gobert AP, Cheng Y, Wang JY, Boucher JL, Iyer RK, Cederbaum SD, Casero RA Jr, Newton JC, Wilson KT (2002a) Helicobacter pylori induces macrophage apoptosis by activation of arginase II. J Immunol 168(9):4692–4700. doi:10.4049/jimmunol.168.9.4692
Gobert AP, Mersey BD, Cheng Y, Blumberg DR, Newton JC, Wilson KT (2002b) Cutting edge: urease release by Helicobacter pylori stimulates macrophage inducible nitric oxide synthase. J Immunol 168(12):6002–6006. doi:10.4049/jimmunol.168.12.6002
Gringhuis SI, den Dunnen J, Litjens M, van der Vlist M, Geijtenbeek TB (2009) Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori. Nat Immunol 10(10):1081–1088. doi:10.1038/ni.1778
Hamanaka Y, Nakashima M, Wada A, Ito M, Kurazono H, Hojo H, Nakahara Y, Kohno S, Hirayama T, Sekine I (2001) Expression of human beta-defensin 2 (hBD-2) in Helicobacter pylori induced gastritis: antibacterial effect of hBD-2 against Helicobacter pylori. Gut 49(4):481–487. doi:10.1136/gut.49.4.481
Harris AG, Hinds FE, Beckhouse AG, Kolesnikow T, Hazell SL (2002) Resistance to hydrogen peroxide in Helicobacter pylori: role of catalase (KatA) and Fur, and functional analysis of a novel gene product designated ‘KatA-associated protein’, KapA (HP0874). Microbiology 148(Pt 12):3813–3825. doi:10.1099/00221287-148-12-3813
Harris AG, Wilson JE, Danon SJ, Dixon MF, Donegan K, Hazell SL (2003) Catalase (KatA) and KatA-associated protein (KapA) are essential to persistent colonization in the Helicobacter pylori SS1 mouse model. Microbiology 149(Pt 3):665–672. doi:10.1099/mic.0.26012-0
Hase K, Murakami M, Iimura M, Cole SP, Horibe Y, Ohtake T, Obonyo M, Gallo RL, Eckmann L, Kagnoff MF (2003) Expression of LL-37 by human gastric epithelial cells as a potential host defense mechanism against Helicobacter pylori. Gastroenterology 125(6):1613–1625. doi:10.1053/j.gastro.2003.08.028
Heneghan MA, McCarthy CF, Moran AP (2000) Relationship of blood group determinants on Helicobacter pylori lipopolysaccharide with host lewis phenotype and inflammatory response. Infect Immun 68(2):937–941. doi:10.1128/IAI.68.2.937-941.2000
IARC (1994) Infection with Helicobacter pylori. IARC monographs on the evaluation of carcinogenic risks to humans/World Health Organization, International Agency for Research on Cancer 61:177–240
Ishihara S, Rumi MA, Kadowaki Y, Ortega-Cava CF, Yuki T, Yoshino N, Miyaoka Y, Kazumori H, Ishimura N, Amano Y, Kinoshita Y (2004) Essential role of MD-2 in TLR4-dependent signaling during Helicobacter pylori-associated gastritis. J Immunol 173(2):1406–1416. doi:10.4049/jimmunol.173.2.1406
Kabir S (2011) The role of interleukin-17 in the Helicobacter pylori induced infection and immunity. Helicobacter 16(1):1–8. doi:10.1111/j.1523-5378.2010.00812.x
Kabisch R, Semper RP, Wustner S, Gerhard M, Mejias-Luque R (2016) Helicobacter pylori gamma-glutamyltranspeptidase induces tolerogenic human dendritic cells by activation of glutamate receptors. J Immunol 196(10):4246–4252. doi:10.4049/jimmunol.1501062
Kaebisch R, Mejias-Luque R, Prinz C, Gerhard M (2014) Helicobacter pylori cytotoxin-associated gene A impairs human dendritic cell maturation and function through IL-10-mediated activation of STAT3. J Immunol 192(1):316–323. doi:10.4049/jimmunol.1302476
Kao JY, Rathinavelu S, Eaton KA, Bai L, Zavros Y, Takami M, Pierzchala A, Merchant JL (2006) Helicobacter pylori-secreted factors inhibit dendritic cell IL-12 secretion: a mechanism of ineffective host defense. Am J Physiol Gastrointest Liver Physiol 291(1):G73–G81. doi:10.1152/ajpgi.00139.2005
Kawahara T, Kohjima M, Kuwano Y, Mino H, Teshima-Kondo S, Takeya R, Tsunawaki S, Wada A, Sumimoto H, Rokutan K (2005) Helicobacter pylori lipopolysaccharide activates Rac1 and transcription of NADPH oxidase Nox1 and its organizer NOXO1 in guinea pig gastric mucosal cells. Am J Physiol Cell Physiol 288(2):C450–C457. doi:10.1152/ajpcell.00319.2004
Kawauchi K, Yagihashi A, Tsuji N, Uehara N, Furuya D, Kobayashi D, Watanabe N (2006) Human beta-defensin-3 induction in H. pylori-infected gastric mucosal tissues. World J Gastroenterol WJG 12(36):5793–5797. doi:10.3748/wjg.v12.i36.5793
Khalifeh Gholi M, Kalali B, Formichella L, Gottner G, Shamsipour F, Zarnani AH, Hosseini M, Busch DH, Shirazi MH, Gerhard M (2013) Helicobacter pylori FliD protein is a highly sensitive and specific marker for serologic diagnosis of H. pylori infection. Int J Med Microbiol IJMM 303(8):618–623. doi:10.1016/j.ijmm.2013.08.005
Kim JM, Kim JS, Yoo DY, Ko SH, Kim N, Kim H, Kim YJ (2011) Stimulation of dendritic cells with Helicobacter pylori vacuolating cytotoxin negatively regulates their maturation via the restoration of E2F1. Clin Exp Immunol 166(1):34–45. doi:10.1111/j.1365-2249.2011.04447.x
Kraft C, Stack A, Josenhans C, Niehus E, Dietrich G, Correa P, Fox JG, Falush D, Suerbaum S (2006) Genomic changes during chronic Helicobacter pylori infection. J Bacteriol 188(1):249–254. doi:10.1128/JB.188.1.249-254.2006
Lebrun AH, Wunder C, Hildebrand J, Churin Y, Zahringer U, Lindner B, Meyer TF, Heinz E, Warnecke D (2006) Cloning of a cholesterol-alpha-glucosyltransferase from Helicobacter pylori. J Biol Chem 281(38):27765–27772. doi:10.1074/jbc.M603345200
Lewis ND, Asim M, Barry DP, Singh K, de Sablet T, Boucher JL, Gobert AP, Chaturvedi R, Wilson KT (2010) Arginase II restricts host defense to Helicobacter pylori by attenuating inducible nitric oxide synthase translation in macrophages. J Immunol 184(5):2572–2582. doi:10.4049/jimmunol.0902436
Ljungh A, Moran AP, Wadstrom T (1996) Interactions of bacterial adhesins with extracellular matrix and plasma proteins: pathogenic implications and therapeutic possibilities. FEMS Immunol Med Microbiol 16(2):117–126. doi:10.1111/j.1574-695X.1996.tb00128.x
Lundgren A, Suri-Payer E, Enarsson K, Svennerholm A-M, Lundin BS (2003) Helicobacter pylori-specific CD4+ CD25high regulatory T cells suppress memory T-cell responses to H. pylori in infected individuals. Infect Immun 71(4):1755–1762. doi:10.1128/IAI.71.4.1755-1762.2003
Michel A, Pawlita M, Boeing H, Gissmann L, Waterboer T (2014) Helicobacter pylori antibody patterns in Germany: a cross-sectional population study. Gut Pathog 6:10. doi:10.1186/1757-4749-6-10
Miszczyk E, Rudnicka K, Moran AP, Fol M, Kowalewicz-Kulbat M, Druszczynska M, Matusiak A, Walencka M, Rudnicka W, Chmiela M (2012) Interaction of Helicobacter pylori with C-type lectin dendritic cell-specific ICAM grabbing nonintegrin. J Biomed Biotechnol 2012:206463. doi:10.1155/2012/206463
Mitchell P, Germain C, Fiori PL, Khamri W, Foster GR, Ghosh S, Lechler RI, Bamford KB, Lombardi G (2007) Chronic exposure to Helicobacter pylori impairs dendritic cell function and inhibits Th1 development. Infect Immun 75(2):810–819. doi:10.1128/IAI.00228-06
Moran AP (2001) Molecular structure, biosynthesis, and pathogenic roles of lipopolysaccharides. In: Mobley HLT, Mendz GL, Hazell SL (eds) Helicobacter pylori: physiology and genetics. ASM Press, Washington (DC). ISBN-10: 1-55581-213-9
Moran AP (2008) Relevance of fucosylation and Lewis antigen expression in the bacterial gastroduodenal pathogen Helicobacter pylori. Carbohydr Res 343(12):1952–1965. doi:10.1016/j.carres.2007.12.012
Moran AP, Aspinall GO (1998) Unique structural and biological features of Helicobacter pylori lipopolysaccharides. Prog Clin Biol Res 397:37–49
Muotiala A, Helander IM, Pyhala L, Kosunen TU, Moran AP (1992) Low biological activity of Helicobacter pylori lipopolysaccharide. Infect Immun 60(4):1714–1716 (0019-9567/92/041714-03$02.00/0)
Necchi V, Manca R, Ricci V, Solcia E (2009) Evidence for transepithelial Dcs in human Hp active gastritis. Helicobacter 14:208–222. doi:10.1111/j.1523-5378.2009.00679.x
Nell S, Kennemann L, Schwarz S, Josenhans C, Suerbaum S (2014) Dynamics of Lewis b binding and sequence variation of the babA adhesin gene during chronic Helicobacter pylori infection in humans. MBio 5(6). doi:10.1128/mBio.02281-14
Nomura AM, Lee J, Stemmermann GN, Nomura RY, Perez-Perez GI, Blaser MJ (2002) Helicobacter pylori CagA seropositivity and gastric carcinoma risk in a Japanese American population. J Infect Dis 186(8):1138–1144. doi:10.1086/343808
Nuding S, Gersemann M, Hosaka Y, Konietzny S, Schaefer C, Beisner J, Schroeder BO, Ostaff MJ, Saigenji K, Ott G, Schaller M, Stange EF, Wehkamp J (2013) Gastric antimicrobial peptides fail to eradicate Helicobacter pylori infection due to selective induction and resistance. PLoS ONE 8(9):e73867. doi:10.1371/journal.pone.0073867
Odenbreit S, Wieland B, Haas R (1996) Cloning and genetic characterization of Helicobacter pylori catalase and construction of a catalase-deficient mutant strain. J Bacteriol 178(23):6960–6967 (0021-9193/96/$04.00)
Oertli M, Noben M, Engler DB, Semper RP, Reuter S, Maxeiner J, Gerhard M, Taube C, Muller A (2013) Helicobacter pylori gamma-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance. Proc Natl Acad Sci USA 110(8):3047–3052. doi:10.1073/pnas.1211248110
Oleastro M, Cordeiro R, Menard A, Gomes JP (2010) Allelic diversity among Helicobacter pylori outer membrane protein genes homB and homA generated by recombination. J Bacteriol 192(15):3961–3968. doi:10.1128/JB.00395-10
Otani K, Tanigawa T, Watanabe T, Nadatani Y, Sogawa M, Yamagami H, Shiba M, Watanabe K, Tominaga K, Fujiwara Y, Arakawa T (2012) Toll-like receptor 9 signaling has anti-inflammatory effects on the early phase of Helicobacter pylori-induced gastritis. Biochem Biophys Res Commun 426(3):342–349. doi:10.1016/j.bbrc.2012.08.080
Pachathundikandi SK, Brandt S, Madassery J, Backert S (2011) Induction of TLR-2 and TLR-5 expression by Helicobacter pylori switches cagPAI-dependent signaling leading to the secretion of IL-8 and TNF-α. PLoS ONE 6:e19614. doi:10.1371/journal.pone.0019614
Pachathundikandi SK, Lind J, Tegtmeyer N, El-Omar EM, Backert S (2015) Interplay of the gastric pathogen Helicobacter pylori with toll-like receptors. Biomed Res Int 2015:192420. doi:10.1155/2015/192420
Pachathundikandi SK, Müller A, Backert S (2016) Inflammasome activation by Helicobacter pylori and its implications for persistence and immunity. Curr Top Microbiol Immunol 397:117–131. doi:10.1007/978-3-319-41171-2_6
Pan KF, Formichella L, Zhang L, Zhang Y, Ma JL, Li ZX, Liu C, Wang YM, Goettner G, Ulm K, Classen M, You WC, Gerhard M (2014) Helicobacter pylori antibody responses and evolution of precancerous gastric lesions in a Chinese population. Int J Cancer 134(9):2118–2125. doi:10.1002/ijc.28560
Patel SR, Smith K, Letley DP, Cook KW, Memon AA, Ingram RJ, Staples E, Backert S, Zaitoun AM, Atherton JC, Robinson K (2013) Helicobacter pylori downregulates expression of human beta-defensin 1 in the gastric mucosa in a type IV secretion-dependent fashion. Cell Microbiol 15(12):2080–2092. doi:10.1111/cmi.12174
Pride DT, Meinersmann RJ, Blaser MJ (2001) Allelic variation within Helicobacter pylori babA and babB. Infect Immun 69(2):1160–1171. doi:10.1128/IAI.69.2.1160-1171.2001
Rad R, Ballhorn W, Voland P, Eisenacher K, Mages J, Rad L, Ferstl R, Lang R, Wagner H, Schmid RM, Bauer S, Prinz C, Kirschning CJ, Krug A (2009) Extracellular and intracellular pattern recognition receptors cooperate in the recognition of Helicobacter pylori. Gastroenterology 136(7):2247–2257. doi:10.1053/j.gastro.2009.02.066
Ramarao N, Meyer TF (2001) Helicobacter pylori resists phagocytosis by macrophages: quantitative assessment by confocal microscopy and fluorescence-activated cell sorting. Infect Immun 69(4):2604–2611. doi:10.1128/IAI.69.4.2604-2611.2001
Ramarao N, Gray-Owen SD, Backert S, Meyer TF (2000a) Helicobacter pylori inhibits phagocytosis by professional phagocytes involving type IV secretion components. Mol Microbiol 37(6):1389–1404. doi:10.1046/j.1365-2958.2000.02089.x
Ramarao N, Gray-Owen SD, Meyer TF (2000b) Helicobacter pylori induces but survives the extracellular release of oxygen radicals from professional phagocytes using its catalase activity. Mol Microbiol 38(1):103–113. doi:10.1046/j.1365-2958.2000.02114.x
Rubin EJ, Trent MS (2013) Colonize, evade, flourish: how glyco-conjugates promote virulence of Helicobacter pylori. Gut Microbes 4(6):439–453. doi:10.4161/gmic.25721
Sayi A, Kohler E, Hitzler I, Arnold I, Schwendener R, Rehrauer H, Muller A (2009) The CD4+ T cell-mediated IFN-gamma response to Helicobacter infection is essential for clearance and determines gastric cancer risk. J Immunol 182(11):7085–7101. doi:10.4049/jimmunol.0803293
Schmees C, Prinz C, Treptau T, Rad R, Hengst L, Voland P, Bauer S, Brenner L, Schmid RM, Gerhard M (2007) Inhibition of T-cell proliferation by Helicobacter pylori gamma-glutamyl transpeptidase. Gastroenterology 132(5):1820–1833. doi:10.1053/j.gastro.2007.02.031
Serelli-Lee V, Ling KL, Ho C, Yeong LH, Lim GK, Ho B, Wong SB (2012) Persistent Helicobacter pylori specific Th17 responses in patients with past H. pylori infection are associated with elevated gastric mucosal IL-1beta. PLoS ONE 7(6):e39199. doi:10.1371/journal.pone.0039199
Sewald X, Gebert-Vogl B, Prassl S, Barwig I, Weiss E, Fabbri M, Osicka R, Schiemann M, Busch DH, Semmrich M, Holzmann B, Sebo P, Haas R (2008) Integrin subunit CD18 is the T-lymphocyte receptor for the Helicobacter pylori vacuolating cytotoxin. Cell Host Microbe 3(1):20–29. doi:10.1016/j.chom.2007.11.003
Sewald X, Jimenez-Soto L, Haas R (2011) PKC-dependent endocytosis of the Helicobacter pylori vacuolating cytotoxin in primary T lymphocytes. Cell Microbiol 13(3):482–496. doi:10.1111/j.1462-5822.2010.01551.x
Seyler RW Jr, Olson JW, Maier RJ (2001) Superoxide dismutase-deficient mutants of Helicobacter pylori are hypersensitive to oxidative stress and defective in host colonization. Infect Immun 69(6):4034–4040. doi:10.1128/IAI.69.6.4034-4040.2001
Shi Y, Liu X-F, Zhuang Y, Zhang J-Y, Liu T, Yin Z, Wu C, Mao X-H, Jia K-R, Wang F-J, Guo H, Flavell RA, Zhao Z, Liu K-Y, Xiao B, Guo Y, Zhang W-J, Zhou W-Y, Guo G, Zou Q-M (2010) Helicobacter pylori-induced Th17 responses modulate Th1 cell responses, benefit bacterial growth, and contribute to pathology in mice. J Immunol 184(9):5121–5129. doi:10.4049/jimmunol.0901115
Shiota S, Murakami K, Okimoto T, Kodama M, Yamaoka Y (2014) Serum Helicobacter pylori CagA antibody titer as a useful marker for advanced inflammation in the stomach in Japan. J Gastroenterol Hepatol 29(1):67–73. doi:10.1111/jgh.12359
Smith SM, Moran AP, Duggan SP, Ahmed SE, Mohamed AS, Windle HJ, O’Neill LA, Kelleher DP (2011) Tribbles 3: a novel regulator of TLR2-mediated signaling in response to Helicobacter pylori lipopolysaccharide. J Immunol 186(4):2462–2471. doi:10.4049/jimmunol.1000864
Solnick JV, Hansen LM, Salama NR, Boonjakuakul JK, Syvanen M (2004) Modification of Helicobacter pylori outer membrane protein expression during experimental infection of rhesus macaques. Proc Natl Acad Sci USA 101(7):2106–2111. doi:10.1073/pnas.0308573100
Spiegelhalder C, Gerstenecker B, Kersten A, Schiltz E, Kist M (1993) Purification of Helicobacter pylori superoxide dismutase and cloning and sequencing of the gene. Infect Immun 61(12):5315–5325 (0019-9567/93/125315-11$02.00/0)
Suerbaum S (2000) Genetic variability within Helicobacter pylori. Int J Med Microbiol IJMM 290(2):175–181. doi:10.1016/S1438-4221(00)80087-9
Sun X, Zhang M, El-Zataari M, Owyang SY, Eaton KA, Liu M, Chang Y-M, Zou W, Kao JY (2013) TLR2 mediates Helicobacter pylori-induced tolerogenic immune response in mice. PLoS ONE 8(9):e74595. doi:10.1371/journal.pone.0074595
Sundrud MS, Torres VJ, Unutmaz D, Cover TL (2004) Inhibition of primary human T cell proliferation by Helicobacter pylori vacuolating toxin (VacA) is independent of VacA effects on IL-2 secretion. Proc Natl Acad Sci USA 101(20):7727–7732. doi:10.1073/pnas.0401528101
Tanaka H, Yoshida M, Nishiumi S, Ohnishi N, Kobayashi K, Yamamoto K, Fujita T, Hatakeyama M, Azuma T (2010) The CagA protein of Helicobacter pylori suppresses the functions of dendritic cell in mice. Arch Biochem Biophys 498(1):35–42. doi:10.1016/j.abb.2010.03.021
Tran AX, Whittimore JD, Wyrick PB, McGrath SC, Cotter RJ, Trent MS (2006) The lipid A 1-phosphatase of Helicobacter pylori is required for resistance to the antimicrobial peptide polymyxin. J Bacteriol 188(12):4531–4541. doi:10.1128/JB.00146-06
Wang J, Brooks EG, Bamford KB, Denning TL, Pappo J, Ernst PB (2001) Negative selection of T cells by Helicobacter pylori as a model for bacterial strain selection by immune evasion. J Immunol 167(2):926–934. doi:10.4049/jimmunol.167.2.926
Wehkamp J, Schmidt K, Herrlinger KR, Baxmann S, Behling S, Wohlschlager C, Feller AC, Stange EF, Fellermann K (2003) Defensin pattern in chronic gastritis: HBD-2 is differentially expressed with respect to Helicobacter pylori status. J Clin Pathol 56(5):352–357. doi:10.1136/jcp.56.5.352
Whitfield C, Trent MS (2014) Biosynthesis and export of bacterial lipopolysaccharides. Annu Rev Biochem 83:99–128. doi:10.1146/annurev-biochem-060713-035600
Wroblewski LE, Peek RM, Wilson KT (2010) Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev 23(4):713–739. doi:10.1128/CMR.00011-10
Wunder C, Churin Y, Winau F, Warnecke D, Vieth M, Lindner B, Zähringer U, Mollenkopf H-J, Heinz E, Meyer TF (2006) Cholesterol glucosylation promotes immune evasion by Helicobacter pylori. Nat Med 12(9):1030–1038. doi:10.1038/nm1480
Wüstner S, Mejías-Luque R, Koch MF, Rath E, Vieth M, Sieber SA, Haller D, Gerhard M (2015) Helicobacter pylori γ-glutamyltranspeptidase impairs T-lymphocyte function by compromising metabolic adaption through inhibition of cMyc and IRF4 expression. Cell Microbiol 17(1):51–61. doi:10.1111/cmi.12335
Yokota S, Ohnishi T, Muroi M, Tanamoto K, Fujii N, Amano K (2007) Highly-purified Helicobacter pylori LPS preparations induce weak inflammatory reactions and utilize Toll-like receptor 2 complex but not Toll-like receptor 4 complex. FEMS Immunol Med Microbiol 51(1):140–148. doi:10.1111/j.1574-695X.2007.00288.x
Zabaleta J, McGee DJ, Zea AH, Hernandez CP, Rodriguez PC, Sierra RA, Correa P, Ochoa AC (2004) Helicobacter pylori arginase inhibits T cell proliferation and reduces the expression of the TCR zeta-chain (CD3zeta). J Immunol 173(1):586–593. doi:10.4049/jimmunol.173.1.586
Zheng PY, Jones NL (2003) Helicobacter pylori strains expressing the vacuolating cytotoxin interrupt phagosome maturation in macrophages by recruiting and retaining TACO (coronin 1) protein. Cell Microbiol 5(1):25–40. doi:10.1046/j.1462-5822.2003.00250.x
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing AG
About this chapter
Cite this chapter
Mejías-Luque, R., Gerhard, M. (2017). Immune Evasion Strategies and Persistence of Helicobacter pylori . In: Tegtmeyer, N., Backert, S. (eds) Molecular Pathogenesis and Signal Transduction by Helicobacter pylori. Current Topics in Microbiology and Immunology, vol 400. Springer, Cham. https://doi.org/10.1007/978-3-319-50520-6_3
Download citation
DOI: https://doi.org/10.1007/978-3-319-50520-6_3
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-50519-0
Online ISBN: 978-3-319-50520-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)