Life in the human stomach: Persistence strategies of the bacterial pathogen Helicobacter pylori

Nature Reviews Microbiology

Volumn 11, Issue 6, 2013, Pages 385-399

  Salama, Nina R ^a   Hartung, Mara L ^b   Müller, Anne ^b  

^a Fred Hutchinson Cancer Research Center   (United States)

^b UNIVERSITY OF ZURICH   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ADHESIN; BACTERIAL PROTEIN; CAGA PROTEIN; CASPASE RECRUITMENT DOMAIN PROTEIN 15; CASPASE RECRUITMENT DOMAIN PROTEIN 4; CXCL1 CHEMOKINE; CYTOTOXIN ASSOCIATED GENE L PROTEIN; FLAGELLIN; GASTRIN; HELICOBACTER PYLORI VACCINE; I KAPPA B; INFLAMMASOME; INTERFERON REGULATORY FACTOR 7; INTERLEUKIN 10; INTERLEUKIN 18 BINDING PROTEIN; INTERLEUKIN 1BETA; PROTEIN P53; REACTIVE OXYGEN METABOLITE; SALMONELLOSIS VACCINE; TOLL LIKE RECEPTOR 2; TOLL LIKE RECEPTOR 3; TOLL LIKE RECEPTOR 5; TRANSCRIPTION FACTOR FOXP3; UNCLASSIFIED DRUG; UVOMORULIN;

ADAPTIVE IMMUNITY; BACTERIAL COLONIZATION; BACTERIAL STRAIN; BACTERIAL VIRULENCE; CD4+ T LYMPHOCYTE; CELL DIFFERENTIATION; CELL MOTILITY; CHEMOTAXIS; CYTOKINE RELEASE; DNA DAMAGE; DNA REPAIR; GENE CONVERSION; GENE DELETION; HELICOBACTER INFECTION; HELICOBACTER PYLORI; HELPER CELL; HOST; HUMAN; HUMORAL IMMUNITY; IMMUNE RESPONSE; IMMUNOBIOLOGY; IMMUNOGENICITY; IMMUNOMODULATION; IN VITRO STUDY; IN VIVO STUDY; INFECTION CONTROL; INFLAMMATION; LIGAND BINDING; NONHUMAN; PATHOGENESIS; PHASE 1 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN DEGRADATION; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN MOTIF; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; REVIEW; RHIZOBIUM RADIOBACTER; SIGNAL TRANSDUCTION; STOMACH; STOMACH CARCINOMA; STOMACH EPITHELIUM; STOMACH MUCOSA; STOMACH PH; TH1 CELL; TH17 CELL; TYPE IV SECRETION SYSTEM;

ADAPTIVE IMMUNITY; GASTRIC MUCOSA; GENE EXPRESSION REGULATION, BACTERIAL; HELICOBACTER INFECTIONS; HELICOBACTER PYLORI; HUMANS; IMMUNITY, INNATE; STOMACH; VIRULENCE FACTORS;

BACTERIA (MICROORGANISMS); HELICOBACTER PYLORI;

EID: 84878013732     PISSN: 17401526     EISSN: 17401534     Source Type: Journal    
DOI: 10.1038/nrmicro3016     Document Type: Review

References (148)

1. Wroblewski, L. E., Peek, R. M. Jr & Wilson, K. T. Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin. Microbiol. Rev. 23, 713-739 (2010).
2. Bik, E. M. et al. Molecular analysis of the bacterial microbiota in the human stomach. Proc. Natl Acad. Sci. USA 103, 732-737 (2006). (Pubitemid 43153094)
3. Palframan, S. L., Kwok, T. & Gabriel, K. Vacuolating cytotoxin A (VacA), a key toxin for Helicobacter pylori pathogenesis. Front. Cell. Infect. Microbiol. 2, 92 (2012).
4. Schreiber, S. et al. Rapid loss of motility of Helicobacter pylori in the gastric lumen in vivo. Infect. Immun. 73, 1584-1589 (2005). (Pubitemid 40470745)
5. Vaishnava, S. et al. The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 334, 255-258 (2011).
6. Montecucco, C. & Rappuoli, R. Living dangerously: how Helicobacter pylori survives in the human stomach. Nature Rev. Mol. Cell Biol. 2, 457-466 (2001). (Pubitemid 33680584)
7. Celli, J. P. et al. Rheology of gastric mucin exhibits a pH-dependent sol-gel transition. Biomacromolecules 8, 1580-1586 (2007). (Pubitemid 46865131)
8. Celli, J. P. et al. Helicobacter pylori moves through mucus by reducing mucin viscoelasticity. Proc. Natl Acad. Sci. USA 106, 14321-14326 (2009). Study showing that H. pylori is immobilized by gastric mucin gel at low pH but in the presence of urea induces a pH-dependent gel-to-solution transition that allows the bacterium to swim freely.
9. Howitt, M. R. et al. ChePep controls Helicobacter pylori infection of the gastric glands and chemotaxis in the Epsilonproteobacteria. mBio 26 Jul 2011 (doi: 10. 1128/mBio. 00098-1).
10. Rolig, A. S., Carter, J. E. & Ottemann, K. M. Bacterial chemotaxis modulates host cell apoptosis to establish a T-helper cell, type 17 (Th17)-dominant immune response in Helicobacter pylori infection. Proc. Natl Acad. Sci. USA 108, 19749-19754 (2011). Study demonstrating that chemotaxis promotes interactions between the bacteria and epithelium that drive pro-inflammatory TH17 responses.
11. Rolig, A. S., Shanks, J., Carter, J. E. & Ottemann, K. M. Helicobacter pylori requires TlpD-driven chemotaxis to proliferate in the antrum. Infect. Immun. 80, 3713-3720 (2012).
12. Terry, K., Williams, S. M., Connolly, L. & Ottemann, K. M. Chemotaxis plays multiple roles during Helicobacter pylori animal infection. Infect. Immun. 73, 803-811 (2005). (Pubitemid 40165736)
13. Bonis, M., Ecobichon, C., Guadagnini, S., Prevost, M. C. & Boneca, I. G. A. M23B family metallopeptidase of Helicobacter pylori required for cell shape, pole formation and virulence. Mol. Microbiol. 78, 809-819 (2010).
14. Sycuro, L. K. et al. Peptidoglycan crosslinking relaxation promotes Helicobacter pylori's helical shape and stomach colonization. Cell 141, 822-833 (2010). References 13 and 14 first identified cell wall enzymes that reduce crosslinking in the cell wall and that promote helical cell shape, which in turn promotes efficient stomach colonization.
15. Sycuro, L. K. et al. Multiple peptidoglycan modification networks modulate Helicobacter pylori's cell shape, motility, and colonization potential. PLoS Pathog. 8, e1002603 (2012).
16. Williams, S. M. et al. Helicobacter pylori chemotaxis modulates inflammation and bacterium-gastric epithelium interactions in infected mice. Infect. Immun. 75, 3747-3757 (2007). (Pubitemid 47206272)
17. Sayi, A. et al. The CD4+ T cell-mediated IFN-gamma response to Helicobacter infection is essential for clearance and determines gastric cancer risk. J. Immunol. 182, 7085-7101 (2009). This paper revealed that T cell responses to H. pylori promote clearance on the one hand and immunopathology on the other hand, which complicates vaccine development.
18. Gobert, A. P. et al. Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: a strategy for bacterial survival. Proc. Natl Acad. Sci. USA 98, 13844-13849 (2001). (Pubitemid 33115986)
19. Wang, G., Alamuri, P. & Maier, R. J. The diverse antioxidant systems of Helicobacter pylori. Mol. Microbiol. 61, 847-860 (2006). (Pubitemid 44134165)
20. Dorer, M. S., Sessler, T. H. & Salama, N. R. Recombination and DNA repair in Helicobacter pylori. Annu. Rev. Microbiol. 65, 329-348 (2011).
21. Chaturvedi, R. et al. Spermine oxidase mediates the gastric cancer risk associated with Helicobacter pylori CagA. Gastroenterology 141, 1696-1708 (2011).
22. Touati, E. et al. Chronic Helicobacter pylori infections induce gastric mutations in mice. Gastroenterology 124, 1408-1419 (2003). (Pubitemid 36531814)
23. Dorer, M. S., Fero, J. & Salama, N. R. DNA damage triggers genetic exchange in Helicobacter pylori. PLoS Pathog. 6, e1001026 (2010).
24. Orillard, E., Radicella, J. P. & Marsin, S. Biochemical and cellular characterization of Helicobacter pylori RecA, a protein with high-level constitutive expression. J. Bacteriol. 193, 6490-6497 (2011).
25. Dorer, M. S., Cohen, I. E., Sessler, T. H., Fero, J. & Salama, N. R. Natural competence promotes Helicobacter pylori chronic infection. Infect. Immun. 81, 209-215 (2012).
26. Aras, R. A., Kang, J., Tschumi, A. I., Harasaki, Y. & Blaser, M. J. Extensive repetitive DNA facilitates prokaryotic genome plasticity. Proc. Natl Acad. Sci. USA 100, 13579-13584 (2003). (Pubitemid 37444783)
27. Aras, R. A. et al. Plasticity of repetitive DNA sequences within a bacterial (Type IV) secretion system component. J. Exp. Med. 198, 1349-1360 (2003). (Pubitemid 37392480)
28. Barrozo, R. M. et al. Functional plasticity in the Type IV secretion system of Helicobacter pylori. PLoS Pathog. 9, e1003189 (2013).
29. Alm, R. A. et al. Comparative genomics of Helicobacter pylori: analysis of the outer membrane protein families. Infect. Immun. 68, 4155-4168 (2000). (Pubitemid 30434570)
30. Colbeck, J. C., Hansen, L. M., Fong, J. M. & Solnick, J. V. Genotypic profile of the outer membrane proteins BabA and BabB in clinical isolates of Helicobacter pylori. Infect. Immun. 74, 4375-4378 (2006). (Pubitemid 43993374)
31. Hennig, E. E., Allen, J. M. & Cover, T. L. Multiple chromosomal loci for the babA gene in Helicobacter pylori. Infect. Immun. 74, 3046-3051 (2006). (Pubitemid 43673021)
32. Solnick, J. V., Hansen, L. M., Salama, N. R., Boonjakuakul, J. K. & Syvanen, M. Modification of Helicobacter pylori outer membrane protein expression during experimental infection of rhesus macaques. Proc. Natl Acad. Sci. USA 101, 2106-2111 (2004). This was the first demonstration of gene conversion as a mechanism for phase variation of adhesin expression during experimental infection. (Pubitemid 38229022)
33. Ilver, D. et al. Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging. Science 279, 373-377 (1998). (Pubitemid 28063371)
34. Kawai, M. et al. Evolution in an oncogenic bacterial species with extreme genome plasticity: Helicobacter pylori East Asian genomes. BMC Microbiol. 11, 104 (2011).
35. Mahdavi, J. et al. Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation. Science 297, 573-578 (2002). (Pubitemid 34815336)
36. Talarico, S., Whitefield, S. E., Fero, J., Haas, R. & Salama, N. R. Regulation of Helicobacter pylori adherence by gene conversion. Mol. Microbiol. 84, 1050-1061 (2012).
37. Styer, C. M. et al. Expression of the BabA adhesin during experimental infection with Helicobacter pylori. Infect. Immun. 78, 1593-1600 (2010).
38. Goodwin, A. C. et al. Expression of the Helicobacter pylori adhesin SabA is controlled via phase variation and the ArsRS signal transduction system. Microbiology 154, 2231-2240 (2008).
39. Salaun, L., Ayraud, S. & Saunders, N. J. Phase variation mediated niche adaptation during prolonged experimental murine infection with Helicobacter pylori. Microbiology 151, 917-923 (2005). (Pubitemid 40425025)
40. Kao, C. Y., Sheu, S. M., Sheu, B. S. & Wu, J. J. Length of thymidine homopolymeric repeats modulates promoter activity of sabA in Helicobacter pylori. Helicobacter 17, 203-209 (2012).
41. Covacci, A. et al. Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer. Proc. Natl Acad. Sci. USA 90, 5791-5795 (1993). (Pubitemid 23176248)
42. Tummuru, M. K., Cover, T. L. & Blaser, M. J. Cloning and expression of a high-molecular-mass major antigen of Helicobacter pylori: evidence of linkage to cytotoxin production. Infect. Immun. 61, 1799-1809 (1993). (Pubitemid 23145878)
43. Murata-Kamiya, N. Pathophysiological functions of the CagA oncoprotein during infection by Helicobacter pylori. Microbes Infect. 13, 799-807 (2011).
44. Ohnishi, N. et al. Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc. Natl Acad. Sci. USA 105, 1003-1008 (2008). A study using transgenic expression to show that CagA can behave as an oncogene. (Pubitemid 351282071)
45. Yamazaki, S. et al. The CagA protein of Helicobacter pylori is translocated into epithelial cells and binds to SHP-2 in human gastric mucosa. J. Infect. Dis. 187, 334-337 (2003). (Pubitemid 36132651)
46. Tsugawa, H. et al. Reactive oxygen species-induced autophagic egradation of Helicobacter pylori CagA is specifically suppressed in cancer stem-like cells. Cell Host Microbe 12, 764-777 (2012). This study defines a molecular interaction by which certain alleles of VacA attenuate CagA activity in cells through autophagy-dependent degradation. These results provide a possible mechanism for the observed association between carriage of CagA and VacA s1m1 alleles. Additionally, the identification of stem-like cells that are resistant to VacA s1m1 autophagy induction indicate a possible CagA-dependent cancer precursor.
47. Ishimoto, T. et al. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth. Cancer Cell 19, 387-400 (2011).
48. Oh, J. D., Karam, S. M. & Gordon, J. I. Intracellular Helicobacter pylori in gastric epithelial progenitors. Proc. Natl Acad. Sci. USA 102, 5186-5191 (2005).
49. Hayashi, T., Morohashi, H. & Hatakeyama, M. Bacterial EPIYA effectors - Where do they come from? What are they? Where are they going? Cell. Microbiol. 15, 377-385 (2012).
50. Mueller, D. et al. c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains. J. Clin. Invest. 122, 1553-1566 (2012). Mutational analysis demonstrating that SRC and ABL family kinases phosphorylate CagA sequentially and in a tightly controlled manner.
51. Israel, D. A. et al. Helicobacter pylori strain-specific differences in genetic content, identified by microarray, influence host inflammatory responses. J. Clin. Invest. 107, 611-620 (2001). (Pubitemid 32205182)
52. Arnold, I. C. et al. Tolerance rather than immunity protects from Helicobacter pylori-induced gastric preneoplasia. Gastroenterology 140, 199-209 (2011).
53. Philpott, D. J. et al. Reduced activation of inflammatory responses in host cells by mouse-adapted Helicobacter pylori isolates. Cell. Microbiol. 4, 285-296 (2002). (Pubitemid 34567596)
54. Tan, S., Noto, J. M., Romero-Gallo, J., Peek, R. M. Jr & Amieva, M. R. Helicobacter pylori perturbs iron trafficking in the epithelium to grow on the cell surface. PLoS Pathog. 7, e1002050 (2011).
55. Terradot, L. & Waksman, G. Architecture of the Helicobacter pylori Cag-type IV secretion system. FEBS J. 278, 1213-1222 (2011).
56. Christie, P. J., Atmakuri, K., Krishnamoorthy, V., Jakubowski, S. & Cascales, E. Biogenesis, architecture, and function of bacterial type IV secretion systems. Annu. Rev. Microbiol. 59, 451-485 (2005). (Pubitemid 41507439)
57. Chandran, V. et al. Structure of the outer membrane complex of a type IV secretion system. Nature 462, 1011-1015 (2009).
58. Fischer, W. et al. Systematic mutagenesis of the Helicobacter pylori cag pathogenicity island: essential genes for CagA translocation in host cells and induction of interleukin-8. Mol. Microbiol. 42, 1337-1348 (2001). (Pubitemid 34209093)
59. Pham, K. T. et al. CagI is an essential component of the Helicobacter pylori Cag type IV secretion system and forms a complex with CagL. PLoS ONE 7, e35341 (2012).
60. Rohde, M., Puls, J., Buhrdorf, R., Fischer, W. & Haas, R. A novel sheathed surface organelle of the Helicobacter pylori cag type IV secretion system. Mol. Microbiol. 49, 219-234 (2003). (Pubitemid 36792016)
61. Tanaka, J., Suzuki, T., Mimuro, H. & Sasakawa, C. Structural definition on the surface of Helicobacter pylori type IV secretion apparatus. Cell. Microbiol. 5, 395-404 (2003). (Pubitemid 36748490)
62. Kwok, T. et al. Helicobacter exploits integrin for type IV secretion and kinase activation. Nature 449, 862-866 (2007). This was the first demonstration that CagL can interact with integrins and has multiple roles in CagA secretion and Cag T4SS-dependent pathological effects on host cells. (Pubitemid 47598611)
63. Conradi, J. et al. An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA. Front. Cell. Infect. Microbiol. 2, 70 (2012).
64. Shaffer, C. L. et al. Helicobacter pylori exploits a unique repertoire of type IV secretion system components for pilus assembly at the bacteria-host cell interface. PLoS Pathog. 7, e1002237 (2011). A study describing robust methods to visualize Cag T4SS pili, revealing that CagA secretion and Cag pilus formation can be uncoupled.
65. Jimenez-Soto, L. F. et al. Helicobacter pylori type IV secretion apparatus exploits beta1 integrin in a novel RGD-independent manner. PLoS Pathog. 5, e1000684 (2009).
66. Kaplan-Turkoz, B. et al. Structural insights into Helicobacter pylori oncoprotein CagA interaction with beta1 integrin. Proc. Natl Acad. Sci. USA 109, 14640-14645 (2012).
67. Gorrell, R. J. et al. A novel NOD1- and CagA-independent pathway of interleukin-8 induction mediated by the Helicobacter pylori type IV secretion system. Cell Microbiol. 26 Oct 2012 (doi: 10. 1111/cmi. 12055).
68. Saha, A., Backert, S., Hammond, C. E., Gooz, M. & Smolka, A. J. Helicobacter pylori CagL activates ADAM17 to induce repression of the gastric H, K-ATPase alpha subunit. Gastroenterology 139, 239-248 (2010).
69. Tegtmeyer, N. et al. A small fibronectin-mimicking protein from bacteria induces cell spreading and focal adhesion formation. J. Biol. Chem. 285, 23515-23526 (2010).
70. Wiedemann, T. et al. Helicobacter pylori CagL dependent induction of gastrin expression via a novel alphavbeta5-integrin-integrin linked kinase signalling complex. Gut 61, 986-996 (2012).
71. Moran, A. P., Lindner, B. & Walsh, E. J. Structural characterization of the lipid A component of Helicobacter pylori rough- and smooth-form lipopolysaccharides. J. Bacteriol. 179, 6453-6463 (1997). (Pubitemid 27443930)
72. Cullen, T. W. et al. Helicobacter pylori versus the host: remodeling of the bacterial outer membrane is required for survival in the gastric mucosa. PLoS Pathog. 7, e1002454 (2012). This paper provides the first description of the H. pylori phosphatases that are responsible for the modification of lipid A that allows escape from TLR4 recognition and mouse colonization.
73. Ishihara, S. et al. Essential role of MD-2 in TLR4-dependent signaling during Helicobacter pylori-associated gastritis. J. Immunol. 173, 1406-1416 (2004). (Pubitemid 38924322)
74. Kawahara, T. et al. Type I Helicobacter pylori lipopolysaccharide stimulates toll-like receptor 4 and activates mitogen oxidase 1 in gastric pit cells. Infect. Immun. 69, 4382-4389 (2001). (Pubitemid 32574436)
75. Yokota, S. et al. 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, 140-148 (2007). (Pubitemid 47387489)
76. Smith, S. M. et al. Tribbles 3: a novel regulator of TLR2-mediated signaling in response to Helicobacter pylori lipopolysaccharide. J. Immunol. 186, 2462-2471 (2011).
77. Rad, R. et al. Extracellular and intracellular pattern recognition receptors cooperate in the recognition of Helicobacter pylori. Gastroenterology 136, 2247-2257 (2009). This article provides a comprehensive analysis of innate immune recognition of H. pylori using dendritic cells from gene-targeted mice lacking various combinations of PRRs.
78. Sayi, A. et al. TLR-2-activated B cells suppress Helicobacter-induced preneoplastic gastric immunopathology by inducing T regulatory-1 cells. J. Immunol. 186, 878-890 (2011).
79. Gewirtz, A. T. et al. Helicobacter pylori flagellin evades toll-like receptor 5-mediated innate immunity. J. Infect. Dis. 189, 1914-1920 (2004). (Pubitemid 38657228)
80. Andersen-Nissen, E. et al. Evasion of Toll-like receptor 5 by flagellated bacteria. Proc. Natl Acad. Sci. USA 102, 9247-9252 (2005). (Pubitemid 40923549)
81. Otani, K. et al. Toll-like receptor 9 signaling has anti-inflammatory effects on the early phase of Helicobacter pylori-induced gastritis. Biochem. Biophys. Res. Commun. 426, 342-349 (2012).
82. Owyang, S. Y., Luther, J., Owyang, C. C., Zhang, M. & Kao, J. Y. Helicobacter pylori DNA's anti-inflammatory effect on experimental colitis. Gut Microbes 3, 168-171 (2012).
83. Luther, J. et al. Helicobacter pylori DNA decreases pro-inflammatory cytokine production by dendritic cells and attenuates dextran sodium sulphate-induced colitis. Gut 60, 1479-1486 (2011).
84. Luther, J., Dave, M., Higgins, P. D. & Kao, J. Y. Association between Helicobacter pylori infection and inflammatory bowel disease: a meta-analysis and systematic review of the literature. Inflamm Bowel Dis. 16, 1077-1084 (2010).
85. Gringhuis, S. I., den Dunnen, J., Litjens, M., van der Vlist, M. & Geijtenbeek, T. B. Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori. Nature Immunol. 10, 1081-1088 (2009).
86. Gringhuis, S. I. et al. C-type lectin DC-SIGN modulates Toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-kappaB. Immunity 26, 605-616 (2007). (Pubitemid 46756345)
87. Strowig, T., Henao-Mejia, J., Elinav, E. & Flavell, R. Inflammasomes in health and disease. Nature 481, 278-286 (2012).
88. Kim, Y. G. et al. The cytosolic sensors Nod1 and Nod2 are critical for bacterial recognition and host defense after exposure to Toll-like receptor ligands. Immunity 28, 246-257 (2008).
89. Broz, P. & Monack, D. M. Molecular mechanisms of inflammasome activation during microbial infections. Immunol. Rev. 243, 174-190 (2011).
90. Viala, J. et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nature Immunol. 5, 1166-1174 (2004). (Pubitemid 39549631)
91. Kaparakis, M. et al. Bacterial membrane vesicles deliver peptidoglycan to NOD1 in epithelial cells. Cell. Microbiol. 12, 372-385 (2009).
92. Hutton, M. L. et al. Helicobacter pylori exploits cholesterol-rich microdomains for induction of NF-kappaB-dependent responses and peptidoglycan delivery in epithelial cells. Infect. Immun. 78, 4523-4531 (2010).
93. Allison, C. C., Kufer, T. A., Kremmer, E., Kaparakis, M. & Ferrero, R. L. Helicobacter pylori induces MAPK phosphorylation and AP-1 activation via a NOD1-dependent mechanism. J. Immunol. 183, 8099-8109 (2009).
94. Grubman, A. et al. The innate immune molecule, NOD1, regulates direct killing of Helicobacter pylori by antimicrobial peptides. Cell. Microbiol. 12, 626-639 (2009).
95. Watanabe, T. et al. NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway. J. Clin. Invest. 120, 1645-1662 (2010). This article provides a description of a new signalling pathway linking NOD1 activation by H. pylori to type I IFN production and infection control.
96. Hitzler, I. et al. Caspase-1 has both proinflammatory and regulatory properties in Helicobacter infections, which are differentially mediated by its substrates IL-1beta and IL-18. J. Immunol. 188, 3594-3602 (2012).
97. Tomita, T. et al. Expression of Interleukin-18, a Th1 cytokine, in human gastric mucosa is increased in Helicobacter pylori infection. J. Infect. Dis. 183, 620-627 (2001). (Pubitemid 32147518)
98. Oertli, M. et al. DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection. J. Clin. Invest. 122, 1082-1096 (2012).
99. Tu, S. et al. Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell 14, 408-419 (2008).
100. El-Omar, E. M. et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404, 398-402 (2000). (Pubitemid 30164342)
101. Benoit, B. N. et al. Role of ASC in the mouse model of Helicobacter pylori infection. J. Histochem. Cytochem. 57, 327-338 (2009).
102. Akhiani, A. A. et al. Protection against Helicobacter pylori infection following immunization is IL-12-dependent and mediated by Th1 cells. J. Immunol. 169, 6977-6984 (2002). (Pubitemid 36899285)
103. Akhiani, A. A., Schon, K., Franzen, L. E., Pappo, J. & Lycke, N. Helicobacter pylori-specific antibodies impair the development of gastritis, facilitate bacterial colonization, and counteract resistance against infection. J. Immunol. 172, 5024-5033 (2004). (Pubitemid 38456429)
104. Ermak, T. H. et al. Immunization of mice with urease vaccine affords protection against Helicobacter pylori infection in the absence of antibodies and is mediated by MHC class II-restricted responses. J. Exp. Med. 188, 2277-2288 (1998). (Pubitemid 29028500)
105. Velin, D., Bachmann, D., Bouzourene, H. & Michetti, P. Mast cells are critical mediators of vaccine-induced Helicobacter clearance in the mouse model. Gastroenterology 129, 142-155 (2005). (Pubitemid 41002051)
106. Velin, D. et al. Interleukin-17 is a critical mediator of vaccine-induced reduction of Helicobacter infection in the mouse model. Gastroenterology 136, 2237-2246 (2009).
107. Hitzler, I., Oertli, M., Becher, B., Agger, E. M. & Mler, A. Dendritic cells prevent. rather than promote immunity conferred by a Helicobacter vaccine using a mycobacterial adjuvant. Gastroenterology 141, 186-196 (2011).
108. Shi, Y. et al. Helicobacter pylori-induced Th17 responses modulate Th1 cell responses, benefit bacterial growth, and contribute to pathology in mice. J. Immunol. 184, 5121-5129 (2010).
109. Stoicov, C. et al. T-bet knockout prevents Helicobacter felis-induced gastric cancer. J. Immunol. 183, 642-649 (2009).
110. Gebert, B., Fischer, W., Weiss, E., Hoffmann, R. & Haas, R. Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science 301, 1099-1102 (2003). (Pubitemid 37022312)
111. Sundrud, M. S., Torres, V. J., Unutmaz, D. & Cover, T. L. 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, 7727-7732 (2004). (Pubitemid 38658097)
112. Sewald, X. et al. Integrin subunit CD18 Is the T-lymphocyte receptor for the Helicobacter pylori vacuolating cytotoxin. Cell Host Microbe 3, 20-29 (2008).
113. Sewald, X., Jimenez-Soto, L. & Haas, R. PKC-dependent endocytosis of the Helicobacter pylori vacuolating cytotoxin in primary T lymphocytes. Cell. Microbiol. 13, 482-496 (2010).
114. Gerhard, M. et al. A secreted low-molecular-weight protein from Helicobacter pylori induces cell-cycle arrest of T cells. Gastroenterology 128, 1327-1339 (2005). (Pubitemid 40712183)
115. Schmees, C. et al. Inhibition of T-cell proliferation by Helicobacter pylori gamma-glutamyl transpeptidase. Gastroenterology 132, 1820-1833 (2007). (Pubitemid 46677933)
116. Oertli, M. et al. Helicobacter pylori gamma-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance. Proc. Natl Acad. Sci. USA 110, 3047-3052 (2013).
117. Kao, J. Y. et al. Helicobacter pylori immune escape is mediated by dendritic cell-induced Treg skewing and Th17 suppression in mice. Gastroenterology 138, 1046-1054 (2010).
118. Kim, J. M. et al. Stimulation of dendritic cells with Helicobacter pylori vacuolating cytotoxin negatively regulates their maturation via the restoration of E2F1. Clin. Exp. Immunol. 166, 34-45 (2011).
119. Lundgren, A. et al. Mucosal FOXP3-expressing CD4+ CD25high regulatory T cells in Helicobacter pylori-infected patients. Infect. Immun. 73, 523-531 (2005). (Pubitemid 40041147)
120. Lundgren, A., Suri-Payer, E., Enarsson, K., Svennerholm, A. M. & Lundin, B. S. Helicobacter pylori-specific CD4+ CD25high regulatory T cells suppress memory T-cell responses to H. pylori in infected individuals. Infect. Immun. 71, 1755-1762 (2003). (Pubitemid 36368704)
121. Lundgren, A., Trollmo, C., Edebo, A., Svennerholm, A. M. & Lundin, B. S. Helicobacter pylori-specific CD4+ T cells home to and accumulate in the human Helicobacter pylori-infected gastric mucosa. Infect. Immun. 73, 5612-5619 (2005). (Pubitemid 41192996)
122. Robinson, K. et al. Helicobacter pylori-induced peptic ulcer disease is associated with inadequate regulatory T cell responses. Gut 57, 1375-1385 (2008). This study demonstrates that asymptomatic carriers predominantly launch TReg responses to H. pylori infection, whereas patients with peptic ulcer disease generate effector T cell responses.
123. Harris, P. R. et al. Helicobacter pylori gastritis in children is associated with a regulatory T-cell response. Gastroenterology 134, 491-499 (2008). (Pubitemid 351173044)
124. Ismail, H. F., Fick, P., Zhang, J., Lynch, R. G. & Berg, D. J. Depletion of neutrophils in IL-10(-/-) mice delays clearance of gastric Helicobacter infection and decreases the Th1 immune response to Helicobacter. J. Immunol. 170, 3782-3789 (2003). (Pubitemid 36359248)
125. Salama, N. R., Otto, G., Tompkins, L. & Falkow, S. Vacuolating cytotoxin of Helicobacter pylori plays a role during colonization in a mouse model of infection. Infect. Immun. 69, 730-736 (2001). (Pubitemid 32109532)
126. Chevalier, C., Thiberge, J. M., Ferrero, R. L. & Labigne, A. Essential role of Helicobacter pylori gamma-glutamyltranspeptidase for the colonization of the gastric mucosa of mice. Mol. Microbiol. 31, 1359-1372 (1999). (Pubitemid 29110095)
127. Blaser, M. J. & Falkow, S. What are the consequences of the disappearing human microbiota? Nature Rev. Microbiol. 7, 887-894 (2009).
128. Amberbir, A. et al. Effects of Helicobacter pylori, geohelminth infection and selected commensal bacteria on the risk of allergic disease and sensitization in 3-year-old Ethiopian children. Clin. Exp. Allergy 41, 1422-1430 (2011).
129. Blaser, M. J., Chen, Y. & Reibman, J. Does Helicobacter pylori protect against asthma and allergy? Gut 57, 561-567 (2008). (Pubitemid 351579962)
130. Chen, Y. & Blaser, M. J. Inverse associations of Helicobacter pylori with asthma and allergy. Arch. Intern. Med. 167, 821-827 (2007). (Pubitemid 46658341)
131. Chen, Y. & Blaser, M. J. Helicobacter pylori colonization is inversely associated with childhood asthma. J. Infect. Dis. 198, 553-560 (2008).
132. Reibman, J. et al. Asthma is inversely associated with Helicobacter pylori status in an urban population. PLoS ONE 3, e4060 (2008).
133. Arnold, I. C. et al. Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells. J. Clin. Invest. 121, 3088-3093 (2011). This paper provides the first experimental evidence of a protective effect of H. pylori infection in allergic asthma.
134. Hayashi, T. et al. Tertiary structure-function analysis reveals the pathogenic signaling potentiation mechanism of Helicobacter pylori oncogenic effector CagA. Cell Host Microbe 12, 20-33 (2012). This study uses a combination of NMR, X-ray crystallography, modelling and mutational analysis to reveal the molecular mechanisms by which CagA interacts with multiple cellular targets.
135. Murata-Kamiya, N., Kikuchi, K., Hayashi, T., Higashi, H. & Hatakeyama, M. Helicobacter pylori exploits host membrane phosphatidylserine for delivery, localization, and pathophysiological action of the CagA oncoprotein. Cell Host Microbe 7, 399-411 (2010).
136. Olbermann, P. et al. A global overview of the genetic and functional diversity in the Helicobacter pylori cag pathogenicity island. PLoS Genet. 6, e1001069 (2010).
137. de Sablet, T. et al. Phylogeographic origin of Helicobacter pylori is a determinant of gastric cancer risk. Gut 60, 1189-1195 (2011).
138. Yeh, Y. C. et al. H. pylori cagL amino acid sequence polymorphism Y58E59 induces a corpus shift of gastric integrin alpha5beta1 related with gastric carcinogenesis. Mol. Carcinog. 50, 751-759 (2011).
139. Rizzato, C. et al. Variations in Helicobacter pylori cytotoxin-associated genes and their influence in progression to gastric cancer: implications for prevention. PLoS ONE 7, e29605 (2012).
140. Rupnow, M. F., Chang, A. H., Shachter, R. D., Owens, D. K. & Parsonnet, J. Cost-effectiveness of a potential prophylactic Helicobacter pylori vaccine in the United States. J. Infect. Dis. 200, 1311-1317 (2009).
141. Muller, A. & Solnick, J. V. Inflammation, immunity, and vaccine development for Helicobacter pylori. Helicobacter 16 (Suppl. 1), 26-32 (2011).
142. Czinn, S. J. & Blanchard, T. Vaccinating against Helicobacter pylori infection. Nature Rev. Gastroenterol. Hepatol 8, 133-140 (2011).
143. Aebischer, T. et al. Correlation of T cell response and bacterial clearance in human volunteers challenged with Helicobacter pylori revealed by randomised controlled vaccination with Ty21a-based Salmonella vaccines. Gut 57, 1065-1072 (2008). This article describes the first human vaccine trial in which volunteers were challenged with live H. pylori; it also provides the first evidence that T cells are required for H. pylori infection control in humans.
144. Malfertheiner, P. et al. Safety and immunogenicity of an intramuscular Helicobacter pylori vaccine in noninfected volunteers: a phase I study. Gastroenterology 135, 787-795 (2008).
145. Linz, B. et al. An African origin for the intimate association between humans and Helicobacter pylori. Nature 445, 915-918 (2007).
146. Howson, C. P., Hiyama, T. & Wynder, E. L. The decline in gastric cancer: epidemiology of an unplanned triumph. Epidemiol. Rev. 8, 1-27 (1986).
147. Herbarth, O. et al. Helicobacter pylori colonisation and eczema. J. Epidemiol. Commun. Health 61, 638-640 (2007). (Pubitemid 46998898)
148. Higgins, P. D. et al. Prior Helicobacter pylori infection ameliorates Salmonella typhimurium-induced colitis: Mucosal crosstalk between stomach and distal intestine. Inflamm. Bowel Dis. 17, 1398-1408 (2010).