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Immune Cell Signaling by Helicobacter pylori: Impact on Gastric Pathology

  • Nicole Blaser
  • Steffen Backert
  • Suneesh Kumar PachathundikandiEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1149)

Abstract

Helicobacter pylori represents a highly successful colonizer of the human stomach. Infections with this Gram-negative bacterium can persist lifelong, and although in the majority of cases colonization is asymptomatic, it can trigger pathologies ranging from chronic gastritis and peptic ulceration to gastric cancer. The interaction of the bacteria with the human host modulates immune responses in different ways to enable bacterial survival and persistence. H. pylori uses various pathogenicity-associated factors such as VacA, NapA, CGT, GGT, lipopolysaccharide, peptidoglycan, heptose 1,7-bisphosphate, ADP-heptose, cholesterol glucosides, urease and a type IV secretion system for controlling immune signaling and cellular functions. It appears that H. pylori manipulates multiple extracellular immune receptors such as integrin-β2 (CD18), EGFR, CD74, CD300E, DC-SIGN, MINCLE, TRPM2, T-cell and Toll-like receptors as well as a number of intracellular receptors including NLRP3, NOD1, NOD2, TIFA and ALPK1. Consequently, downstream signaling pathways are hijacked, inducing tolerogenic dendritic cells, inhibiting effector T cell responses and changing the gastrointestinal microbiota. Here, we discuss in detail the interplay of bacterial factors with multiple immuno-regulatory cells and summarize the main immune evasion and persistence strategies employed by H. pylori.

Keywords

T4SS TLR PAMP PRR Inflammasome 

Notes

Acknowledgments

This work was supported by grant A04 in CRC-1181 of the German Science Foundation (DFG) to S.B.

Conflict of Interest

The authors declare no conflict of interest.

References

  1. Allen LA (2007) Phagocytosis and persistence of Helicobacter pylori. Cell Microbiol 9(4):817–828.  https://doi.org/10.1111/j.1462-5822.2007.00906.x CrossRefPubMedGoogle Scholar
  2. Allison CC, Kufer TA, Kremmer E, Kaparakis M, Ferrero RL (2009) Helicobacter pylori induces MAPK phosphorylation and AP-1 activation via a NOD1-dependent mechanism. J Immunol 183(12):8099–8109.  https://doi.org/10.4049/jimmunol.0900664 CrossRefPubMedGoogle Scholar
  3. Allison CC, Ferrand J, McLeod L, Hassan M, Kaparakis-Liaskos M, Grubman A, Bhathal PS, Dev A, Sievert W, Jenkins BJ, Ferrero RL (2013) Nucleotide oligomerization domain 1 enhances IFN-γ signaling in gastric epithelial cells during Helicobacter pylori infection and exacerbates disease severity. J Immunol 190(7):3706–3715.  https://doi.org/10.4049/jimmunol.1200591 CrossRefPubMedGoogle Scholar
  4. Amedei A, Cappon A, Codolo G, Cabrelle A, Polenghi A, Benagiano M, Tasca E, Azzurri A, D’Elios MM, Del Prete G, de Bernard M (2006) The neutrophil-activating protein of Helicobacter pylori promotes Th1 immune responses. J Clin Invest 116(4):1092–1101.  https://doi.org/10.1172/JCI27177 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Asano N, Imatani A, Watanabe T, Fushiya J, Kondo Y, Jin X, Ara N, Uno K, Iijima K, Koike T, Strober W, Shimosegawa T (2016) Cdx2 expression and intestinal metaplasia induced by Helicobacter pylori infection of gastric cells is regulated by NOD1-mediated innate immune responses. Cancer Res 76(5):1135–1145.  https://doi.org/10.1158/0008-5472.CAN-15-2272 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Backert S (2016) Inflammasome signaling and bacterial infections, 1st edn. Springer, Heidelberg, pp 1–22.  https://doi.org/10.1007/978-3-319-41171-2 CrossRefGoogle Scholar
  7. Backert S, Naumann M (2010) What a disorder: proinflammatory signaling pathways induced by helicobacter pylori. Trends Microbiol 18(11):479–486.  https://doi.org/10.1016/j.tim.2010.08.003 CrossRefPubMedGoogle Scholar
  8. Backert S, Ziska E, Brinkmann V, Zimny-Arndt U, Fauconnier A, Jungblut PR, Naumann M, Meyer TF (2000) Translocation of the Helicobacter pylori CagA protein in gastric epithelial cells by a type IV secretion apparatus. Cell Microbiol 2(2):155–164.  https://doi.org/10.1046/j.1462-5822.2000.00043.x CrossRefPubMedGoogle Scholar
  9. Backert S, Clyne M, Tegtmeyer N (2011) Molecular mechanisms of gastric epithelial cell adhesion and injection of CagA by Helicobacter pylori. Cell Commun Signal 9:28.  https://doi.org/10.1186/1478-811X-9-28 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Backert S, Schmidt TP, Harrer A, Wessler S (2017) Exploiting the gastric epithelial barrier: Helicobacter pylori’s attack on tight and adherens junctions. Curr Top Microbiol Immunol 400:195–226.  https://doi.org/10.1007/978-3-319-50520-6_9 CrossRefPubMedGoogle Scholar
  11. Backert S, Bernegger S, Skórko-Glonek J, Wessler S (2018) Extracellular HtrA serine proteases: an emerging new strategy in bacterial pathogenesis. Cell Microbiol 20(6):e12845.  https://doi.org/10.1111/cmi.12845 CrossRefPubMedGoogle Scholar
  12. Barden S, Lange S, Tegtmeyer N, Conradi J, Sewald N, Backert S, Niemann HH (2013) A helical RGD motif promoting cell adhesion: crystal structures of the Helicobacter pylori type IV secretion system pilus protein CagL. Structure 21(11):1931–1941.  https://doi.org/10.1016/j.str.2013.08.018 CrossRefPubMedGoogle Scholar
  13. Bauer B, Meyer TF (2011) The human gastric pathogen Helicobacter pylori and its association with gastric cancer and ulcer disease. Ulcers 2011:1–23.  https://doi.org/10.1155/2011/340157 CrossRefGoogle Scholar
  14. Beceiro S, Radin JN, Chatuvedi R, Piazuelo MB, Horvarth DJ, Cortado H, Gu Y, Dixon B, Gu C, Lange I, Koomoa DL, Wilson KT, Algood HM, Partida-Sánchez S (2017) TRPM2 ion channels regulate macrophage polarization and gastric inflammation during Helicobacter pylori infection. Mucosal Immunol 10(2):493–507.  https://doi.org/10.1038/mi.2016.60 CrossRefPubMedGoogle Scholar
  15. Bergman MP, Engering A, Smits HH, van Vliet SJ, van Bodegraven AA, Wirth HP, Kapsenberg ML, Vandenbroucke-Grauls CM, 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.  https://doi.org/10.1084/jem.20041061 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Beswick EJ, Reyes VE (2009) CD74 in antigen presentation, inflammation, and cancers of the gastrointestinal tract. World J Gastroenterol 15(23):2855–2861.  https://doi.org/10.3748/wjg.15.2855 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Beswick EJ, Das S, Pinchuk IV, Adegboyega P, Suarez G, Yamaoka Y, Reyes VE (2005) Helicobacter pylori-induced IL-8 production by gastric epithelial cells up-regulates CD74 expression. J Immunol 175(1):171–176.  https://doi.org/10.4049/jimmunol.175.1.171 CrossRefPubMedGoogle Scholar
  18. Beswick EJ, Pinchuk IV, Das S, Powell DW, Reyes VE (2007) Expression of the programmed death ligand 1, B7-H1, on gastric epithelial cells after Helicobacter pylori exposure promotes development of CD4+ CD25+ FoxP3+ regulatory T cells. Infect Immun 75(9):4334–4341.  https://doi.org/10.1128/IAI.00553-07 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Beutler BA (2009) TLRs and innate immunity. Blood 113(7):1399–1407.  https://doi.org/10.1182/blood-2008-07-019307 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 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.  https://doi.org/10.1084/jem.20030621 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Boonyanugomol W, Chomvarin C, Hahnvajanawong C, Sripa B, Kaparakis-Liaskos M, Ferrero RL (2013) Helicobacter pylori cag pathogenicity island (cagPAI) involved in bacterial internalization and IL-8 induced responses via NOD1- and MyD88-dependent mechanisms in human biliary epithelial cells. PLoS One 8:e77358.  https://doi.org/10.1371/journal.pone.0077358 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Borlace GN, Butler RN, Brooks DA (2008) Monocyte and macrophage killing of Helicobacter pylori: relationship to bacterial virulence factors. Helicobacter 13:380–387.  https://doi.org/10.1111/j.1523-5378.2008.00625.x CrossRefPubMedGoogle Scholar
  23. Borlace GN, Jones HF, Keep SJ, Butler RN, Brooks DA (2011) Helicobacter pylori phagosome maturation in primary human macrophages. Gut Pathog 3(1):3.  https://doi.org/10.1186/1757-4749-3-3 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Brandt S, Kwok T, Hartig R, König W, Backert S (2005) NF-kappaB activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein. Proc Natl Acad Sci U S A 102(26):9300–9305.  https://doi.org/10.1073/pnas.0409873102 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Braun DA, Fribourg M, Sealfon SC (2013) Cytokine response is determined by duration of receptor and signal transducers and activators of transcription 3 (STAT3) activation. J Biol Chem 288:2986–2993.  https://doi.org/10.1074/jbc.M112.386573 CrossRefPubMedGoogle Scholar
  26. Bridge DR, Merrell DS (2013) Polymorphism in the Helicobacter pylori CagA and VacA toxins and disease. Gut Microbes 4:101–117.  https://doi.org/10.4161/gmic.23797 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Brisslert M, Enarsson K, Lundin S, Karlsson A, Kusters JG, Svennerholm AM, Backert S, Quiding-Järbrink M (2005) Helicobacter pylori induce neutrophil transendothelial migration: role of the bacterial HP-NAP. FEMS Microbiol Lett 249(1):95–103.  https://doi.org/10.1016/j.femsle.2005.06.008 CrossRefPubMedGoogle Scholar
  28. Brownlie RJ, Zamoyska R (2013) T cell receptor signaling networks: branched, diversified and bounded. Nat Rev Immunol 13:257–269.  https://doi.org/10.1038/nri3403 CrossRefPubMedGoogle Scholar
  29. Calore F, Genisset C, Casellato A, Rossato M, Codolo G, Esposti MD, Scorrano L, de Bernard M (2010) Endosome-mitochondria juxtaposition during apoptosis induced by H pylori VacA. Cell Death Differ 17:1707–1716.  https://doi.org/10.1038/cdd.2010.42 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Carr EL, Kelman A, Wu GS, Gopaul R, Senkevitch E, Aghvanyan A, Turay AM, Frauwirth KA (2010) Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J Immunol 185:1037–1044.  https://doi.org/10.4049/jimmunol.0903586 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Chang LL, Wang SW, Wu IC, Yu FJ, Su YC, Chen YP, Wu DC, Kuo CH, Hung CH (2012) Impaired dendritic cell maturation and IL-10 production following H. pylori stimulation in gastric cancer patients. Appl Microbiol Biotechnol 96(1):211–220.  https://doi.org/10.1007/s00253-012-4034-z CrossRefPubMedPubMedCentralGoogle Scholar
  32. Chevalier C, Thiberge JM, Ferrero RL, Labigne A (1999) Essential role of Helicobacter pylori gamma-glutamyltranspeptidase for the colonization of the gastric mucosa of mice. Mol Microbiol 31:1359–1372.  https://doi.org/10.1046/j.1365-2958.1999.01271.x CrossRefPubMedGoogle Scholar
  33. Chiou CC, Chan CC, Kuo YP, Chan EC (2003) Helicobacter pylori inhibits activity of cdc2 kinase and delays G2/M to G1 progression in gastric adenocarcinoma cell line. Scand J Gastroenterol 38(2):147–152.  https://doi.org/10.1080/00365520310000627 CrossRefPubMedGoogle Scholar
  34. Collaborative Computational Project, Number 4 (1994) The CCP4 suite: programs for protein crystallography. Acta Crystallogr Sect D Biol Crystallogr 50:760–763.  https://doi.org/10.1107/S0907444994003112 CrossRefGoogle Scholar
  35. Conradi J, Tegtmeyer N, Woźna M, Wissbrock M, Michalek C, Gagell C, Cover TL, Frank R, Sewald N, Backert S (2012) An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA. Front Cell Infect Microbiol 2:70.  https://doi.org/10.3389/fcimb.2012.00070 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Cook KW, Letley DP, Ingram RJ, Staples E, Skjoldmose H, Atherton JC, Robinson K (2014) CCL20/CCR6-mediated migration of regulatory T cells to the Helicobacter pylori-infected human gastric mucosa. Gut 63:1550–1559.  https://doi.org/10.1136/gutjnl-2013-306253 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Cover TL, Krishna US, Israel DA, Peek RM (2003) Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin. Cancer Res 63(5):951–957PubMedGoogle Scholar
  38. 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 158:962–967PubMedGoogle Scholar
  39. Das S, Suarez G, Beswick EJ, Sierra JC, Graham DY, Reyes VE (2006) Expression of B7-H1 on gastric epithelial cells: its potential role in regulating T cells during Helicobacter pylori infection. J Immunol 176:3000–3009.  https://doi.org/10.4049/jimmunol.176.5.3000 CrossRefPubMedGoogle Scholar
  40. Das L, Kokate SB, Rath S, Rout N, Singh SP, Crowe SE, Mukhopadhyay AK, Bhattacharyya A (2016) ETS2 and Twist1 promote invasiveness of Helicobacter pylori-infected gastric cancer cells by inducing Siah2. Biochem J 473(11):1629–1640.  https://doi.org/10.1042/BCJ20160187 CrossRefPubMedPubMedCentralGoogle Scholar
  41. De Bruyne E, Ducatelle R, Foss D, Sanchez M, Joosten M, Zhang G, Smet A, Pasmans F, Haesebrouck F, Flahou B (2016) Oral glutathione supplementation drastically reduces Helicobacter-induced gastric pathologies. Sci Rep 6:20169.  https://doi.org/10.1038/srep20169 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Del Giudice G, Covacci A, Telford JL, Montecucco C, Rappuoli R (2001) The design of vaccines against Helicobacter pylori and their development. Annu Rev Immunol 19:523–563.  https://doi.org/10.1146/annurev.immunol.19.1.523 CrossRefPubMedGoogle Scholar
  43. 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.  https://doi.org/10.1038/srep15049 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Dinarello CA (2009) Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 27:519–550.  https://doi.org/10.1146/annurev.immunol.021908.132612 CrossRefGoogle Scholar
  45. Du SY, Wang HJ, Cheng HH, Chen SD, Wang LH, Wang WC (2016) Cholesterol glucosylation by Helicobacter pylori delays internalization and arrests phagosome maturation in macrophages. J Microbiol Immunol Infect 49:636–645.  https://doi.org/10.1016/j.jmii.2014.05.011 CrossRefPubMedGoogle Scholar
  46. Dundon WG, de Bernard M, Montecucco C (2001) Virulence factors of Helicobacter pylori. Int J Med Microbiol 290(8):647–658.  https://doi.org/10.1016/S1438-4221(01)80002-3 CrossRefPubMedGoogle Scholar
  47. Dunn BE, Cohen H, Blaser MJ (1997) Helicobacter pylori. Clin Microbiol Rev 10(4):720–741CrossRefGoogle Scholar
  48. Galgani M, Busiello I, Censini S, Zappacosta S, Racioppi L, Zarrilli R (2004) Helicobacter pylori induces apoptosis of human monocytes but not monocyte-derived dendritic cells: role of the cag pathogenicity island. Infect Immun 72:4480–4485.  https://doi.org/10.1128/IAI.72.8.4480-4485.2004 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Gall A, Gaudet RG, Gray-Owen SD, Salama NR (2017) TIFA signaling in gastric epithelial cells initiates the cag type 4 secretion system-dependent innate immune response to Helicobacter pylori infection. MBio 8(4). pii: e01168–17.  https://doi.org/10.1128/mBio.01168-17
  50. Garhart CA, Redline RW, Nedrud JG, Czinn SJ (2002) Clearance of Helicobacter pylori infection and resolution of postimmunization gastritis in a kinetic study of prophylactically immunized mice. Infect Immun 70:3529–3538.  https://doi.org/10.1128/IAI.70.7.3529-3538.2002 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Gauthier NC, Monzo P, Kaddai V, Doye A, Ricci V, Boquet P (2005) Helicobacter pylori VacA cytotoxin: a probe for a clathrin-independent and Cdc42-dependent pinocytic pathway routed to late endosomes. Mol Biol Cell 16:4852–4866.  https://doi.org/10.1091/mbc.E05-05-0398 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Gebert B, Fischer W, Weiss E, Hoffmann R, Haas R (2003) Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science 301:1099–1102.  https://doi.org/10.1126/science.1086871 CrossRefPubMedGoogle Scholar
  53. 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.  https://doi.org/10.1053/J.GASTRO.2005.03.018 CrossRefPubMedGoogle Scholar
  54. Gieseler S, König B, König W, Backert S (2005) Strain-specific expression profiles of virulence genes in Helicobacter pylori during infection of gastric epithelial cells and granulocytes. Microbes Infect 7(3):437–447.  https://doi.org/10.1016/j.micinf.2004.11.018 CrossRefPubMedGoogle Scholar
  55. Go MF (1997) What are the host factors that place an individual at risk for Helicobacter pylori-associated disease. Gastroenterology 113:S15–S20.  https://doi.org/10.1016/S0016-5085(97)80005-4 CrossRefPubMedGoogle Scholar
  56. Gobert AP, Wilson KT (2016) The immune battle against Helicobacter pylori infection: NO offense. Trends Microbiol 24(5):366–376.  https://doi.org/10.1016/j.tim.2016.02.005 CrossRefPubMedPubMedCentralGoogle Scholar
  57. Gobert AP, Verriere T, Asim M, Barry DP, Piazuelo MB, de Sablet T, Delgado AG, Bravo LE, Correa P, Peek RM Jr, Chaturvedi R, Wilson KT (2014) Heme oxygenase-1 dysregulates macrophage polarization and the immune response to Helicobacter pylori. J Immunol 193(6):3013–3022.  https://doi.org/10.4049/jimmunol.1401075 CrossRefPubMedPubMedCentralGoogle Scholar
  58. González-Rivera C, Algood HMS, Radin JN, McClain MS, Cover TL (2012) The intermediate region of Helicobacter pylori VacA is a determinant of toxin potency in a Jurkat T cell assay. Infect Immun 80:2578–2588.  https://doi.org/10.1128/IAI.00052-12 CrossRefPubMedPubMedCentralGoogle Scholar
  59. Gorrell RJ, Guan J, Xin Y, Tafreshi MA, Hutton ML, McGuckin MA, Ferrero RL, Kwok T (2013) A novel NOD1- and CagA-independent pathway of interleukin-8 induction mediated by the Helicobacter pylori type IV secretion system. Cell Microbiol 15(4):554–570.  https://doi.org/10.1111/cmi.12055 CrossRefPubMedGoogle Scholar
  60. Gringhuis SI, den Dunnen J, Litjens M, van Het Hof B, van Kooyk Y, Geijtenbeek TB (2007) C-type lectin DC-SIGN modulates toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-kappaB. Immunity 26(5):605–616.  https://doi.org/10.1016/j.immuni.2007.03.012 CrossRefPubMedGoogle Scholar
  61. 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.  https://doi.org/10.1038/ni.1778 CrossRefPubMedGoogle Scholar
  62. Gringhuis SI, Kaptein TM, Wevers BA, Mesman AW, Geijtenbeek TB (2014) Fucose-specific DC-SIGN signalling directs T helper cell type-2 responses via IKKε- and CYLD-dependent Bcl3 activation. Nat Commun 5:3898.  https://doi.org/10.1038/ncomms4898 CrossRefPubMedGoogle Scholar
  63. Hirata Y, Maeda S, Mitsuno Y, Tateishi K, Yanai A, Akanuma M, Yoshida H, Kawabe T, Shiratori Y, Omata M (2002) Helicobacter pylori CagA protein activates serum response element-driven transcription independently of tyrosine phosphorylation. Gastroenterology 123(6):1962–1971.  https://doi.org/10.1053/gast.2002.37044 CrossRefPubMedGoogle Scholar
  64. Horvath DJ Jr, Washington MK, Cope VA, Algood HM (2012) IL-23 contributes to control of chronic Helicobacter pylori infection and the development of T helper responses in a mouse model. Front Immunol 3:56.  https://doi.org/10.3389/fimmu.2012.00056 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Horvath DJ Jr, Radin JN, Cho SH, Washington MK, Algood HM (2013) The interleukin-17 receptor B subunit is essential for the Th2 response to Helicobacter pylori, but not for control of bacterial burden. PLoS One 8(3):e60363.  https://doi.org/10.1371/journal.pone.0060363 CrossRefPubMedPubMedCentralGoogle Scholar
  66. Hussain K, Letley DP, Greenaway AB, Kenefeck R, Winter JA, Tomlinson W, Rhead J, Staples E, Kaneko K, Atherton JC, Robinson K (2016) Helicobacter pylori-mediated protection from allergy is associated with IL-10-secreting peripheral blood regulatory T cells. Front Immunol 7:71.  https://doi.org/10.3389/fimmu.2016.00071 CrossRefPubMedPubMedCentralGoogle Scholar
  67. Hutton ML, Kaparakis-Liaskos M, Turner L, Cardona A, Kwok T, Ferrero RL (2010) Helicobacter pylori exploits cholesterol-rich microdomains for induction of NF-kappaB-dependent responses and peptidoglycan delivery in epithelial cells. Infect Immun 78(11):4523–4531.  https://doi.org/10.1128/IAI.00439-10 CrossRefPubMedPubMedCentralGoogle Scholar
  68. Hutton ML, D’Costa K, Rossiter AE, Wang L, Turner L, Steer DL, Masters SL, Croker BA, Kaparakis-Liaskos M, Ferrero RL (2017) A Helicobacter pylori homolog of eukaryotic flotillin is involved in cholesterol accumulation, epithelial cell responses and host colonization. Front Cell Infect Microbiol 6(7):219.  https://doi.org/10.3389/fcimb.2017.00219 CrossRefGoogle Scholar
  69. 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 173:1406–1416.  https://doi.org/10.4049/jimmunol.173.2.1406 CrossRefPubMedGoogle Scholar
  70. Jo Y, Han SU, Kim YJ, Kim JH, Kim ST, Kim SJ, Hahm KB (2010) Suppressed gastric mucosal TGF-beta1 increases susceptibility to H. pylori-induced gastric inflammation and ulceration: a stupid host defense response. Gut Liver 4(1):43–53.  https://doi.org/10.5009/gnl.2010.4.1.43 CrossRefPubMedPubMedCentralGoogle Scholar
  71. Käbisch R, Mejías-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 192:316–323.  https://doi.org/10.4049/jimmunol.1302476 CrossRefGoogle Scholar
  72. Käbisch R, Semper RP, Wüstner S, Gerhard M, Mejías-Luque R (2016) Helicobacter pylori γ-glutamyltranspeptidase induces tolerogenic human dendritic cells by activation of glutamate receptors. J Immunol 196:4246–4252.  https://doi.org/10.4049/jimmunol.1501062 CrossRefPubMedGoogle Scholar
  73. Kao JY, Zhang M, Miller MJ, Mills JC, Wang B, Liu M, Eaton KA, Zou W, Berndt BE, Cole TS, Takeuchi T, Owyang SY, Luther J (2010) Helicobacter pylori immune escape is mediated by dendritic cell–induced Treg skewing and Th17 suppression in mice. Gastroenterology 138:1046–1054.  https://doi.org/10.1053/J.GASTRO.2009.11.043 CrossRefGoogle Scholar
  74. Kaparakis M, Turnbull L, Carneiro L, Firth S, Coleman HA, Parkington HC, Le Bourhis L, Karrar A, Viala J, Mak J, Hutton ML, Davies JK, Crack PJ, Hertzog PJ, Philpott DJ, Girardin SE, Whitchurch CB, Ferrero RL (2010) Bacterial membrane vesicles deliver peptidoglycan to NOD1 in epithelial cells. Cell Microbiol 12:372–385.  https://doi.org/10.1111/j.1462-5822.2009.01404.x CrossRefPubMedGoogle Scholar
  75. Kim JM, Kim JS, Lee JY, Kim YJ, Youn HJ, Kim IY, Chee YJ, Oh YK, Kim N, Jung HC, Song IS (2007a) Vacuolating cytotoxin in Helicobacter pylori water-soluble proteins upregulates chemokine expression in human eosinophils via Ca2+ influx, mitochondrial reactive oxygen intermediates, and NF-kappaB activation. Infect Immun 75:3373–3381.  https://doi.org/10.1128/IAI.01940-06 CrossRefPubMedPubMedCentralGoogle Scholar
  76. Kim KM, Lee SG, Park MG, Song JY, Kang HL, Lee WK, Cho MJ, Rhee KH, Youn HS, Baik SC (2007b) γ-Glutamyltranspeptidase of Helicobacter pylori induces mitochondria-mediated apoptosis in AGS cells. Biochem Biophys Res Commun 355:562–567.  https://doi.org/10.1016/J.BBRC.2007.02.021 CrossRefPubMedGoogle Scholar
  77. Kim JM, Kim JS, Lee JY, Sim YS, Kim YJ, Oh YK, Yoon HJ, Kang JS, Youn J, Kim N, Jung HC, Kim S (2010) Dual effects of Helicobacter pylori vacuolating cytotoxin on human eosinophil apoptosis in early and late periods of stimulation. Eur J Immunol 40:1651–1662.  https://doi.org/10.1002/eji.200939882 CrossRefPubMedGoogle Scholar
  78. 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 166:34–45.  https://doi.org/10.1111/j.1365-2249.2011.04447.x CrossRefPubMedPubMedCentralGoogle Scholar
  79. Kim SH, Sierra RA, McGee DJ, Zabaleta J (2012) Transcriptional profiling of gastric epithelial cells infected with wild type or arginase-deficient Helicobacter pylori. BMC Microbiol 12:175.  https://doi.org/10.1186/1471-2180-12-175 CrossRefPubMedPubMedCentralGoogle Scholar
  80. Kim DJ, Park JH, Franchi L, Backert S, Núñez G (2013) The cag pathogenicity island and interaction between TLR2/NOD2 and NLRP3 regulate IL-1β production in Helicobacter pylori infected dendritic cells. Eur J Immunol 43(10):2650–2658.  https://doi.org/10.1002/eji.201243281 CrossRefPubMedPubMedCentralGoogle Scholar
  81. Kim BJ, Kim JY, Hwang ES, Kim JG (2015a) Nucleotide binding oligomerization domain 1 is an essential signal transducer in human epithelial cells infected with Helicobacter pylori that induces the transepithelial migration of neutrophils. Gut Liver 9:358–369.  https://doi.org/10.5009/gnl13218 CrossRefPubMedGoogle Scholar
  82. Kim JM, Kim JS, Kim N, Ko SH, Jeon JI, Kim YJ (2015b) Helicobacter pylori vacuolating cytotoxin induces apoptosis via activation of endoplasmic reticulum stress in dendritic cells. J Gastroenterol Hepatol 30:99–108.  https://doi.org/10.1111/jgh.12663 CrossRefPubMedGoogle Scholar
  83. Koch KN, Hartung ML, Urban S, Kyburz A, Bahlmann AS, Lind J, Backert S, Taube C, Müller A (2015) Helicobacter urease-induced activation of the TLR2/NLRP3/IL-18 axis protects against asthma. J Clin Invest 125:3297–3302.  https://doi.org/10.1172/JCI79337 CrossRefPubMedPubMedCentralGoogle Scholar
  84. Kranzer K, Söllner L, Aigner M, Lehn N, Deml L, Rehli M, Schneider-Brachert W (2005) Impact of Helicobacter pylori virulence factors and compounds on activation and maturation of human dendritic cells. Infect Immun 73:4180–4189.  https://doi.org/10.1128/IAI.73.7.4180-4189.2005 CrossRefPubMedPubMedCentralGoogle Scholar
  85. Kwok T, Zabler D, Urman S, Rohde M, Hartig R, Wessler S, Misselwitz R, Berger J, Sewald N, König W, Backert S (2007) Helicobacter exploits integrin for type IV secretion and kinase activation. Nature 449:862–866.  https://doi.org/10.1038/nature06187 CrossRefPubMedGoogle Scholar
  86. Lai CH, Chang YC, Du SY, Wang HJ, Kuo CH, Fang SH, Fu HW, Lin HH, Chiang AS, Wang WC (2008) Cholesterol depletion reduces Helicobacter pylori CagA translocation and CagA-induced responses in AGS cells. Infect Immun 76:3293–3303.  https://doi.org/10.1128/IAI.00365-08 CrossRefPubMedPubMedCentralGoogle Scholar
  87. Lai CH, Wang HJ, Chang YC, Hsieh WC, Lin HJ, Tang CH, Sheu JJ, Lin CJ, Yang MS, Tseng SF, Wang WC (2011) Helicobacter pylori CagA-mediated IL-8 induction in gastric epithelial cells is cholesterol-dependent and requires the C-terminal tyrosine phosphorylation-containing domain. FEMS Microbiol Lett 323(2):155–163.  https://doi.org/10.1111/j.1574-6968.2011.02372.x CrossRefPubMedGoogle Scholar
  88. Lew DJ, Dulić V, Reed SI (1991) Isolation of three novel human cyclins by rescue of G1 cyclin (cln) function in yeast. Cell 66:1197–1206.  https://doi.org/10.1016/0092-8674(91)90042-W CrossRefPubMedGoogle Scholar
  89. Li N, Xie C, Lu NH (2015) Transforming growth factor-β: an important mediator in Helicobacter pylori-associated pathogenesis. Front Cell Infect Microbiol 5:77.  https://doi.org/10.3389/fcimb.2015.00077 CrossRefPubMedPubMedCentralGoogle Scholar
  90. Liu X, Berry CT, Ruthel G, Madara JJ, MacGillivray K, Gray CM, Madge LA, McCorkell KA, Breiting DP, Hershberg U, May MJ, Freedman BD (2016) T cell receptor-induced nuclear factor κB (NF-κB) signaling and transcriptional activation are regulated by STIM1- and Orai1-mediated calcium entry. J Biol Chem 291(16):8440–8452.  https://doi.org/10.1074/jbc.M115.713008 CrossRefPubMedPubMedCentralGoogle Scholar
  91. Maeda S, Akanuma M, Mitsuno Y, Hirata Y, Ogura K, Yoshida H, Shiratori Y, Omata M (2001) Distinct mechanism of Helicobacter pylori-mediated NF-kappa B activation between gastric cancer cells and monocytic cells. J Biol Chem 276:44856–44864.  https://doi.org/10.1074/jbc.M105381200 CrossRefPubMedGoogle Scholar
  92. Mai UE, Perez-Perez GI, Wahl LM, Wahl SM, Blaser MJ, Smith PD (1991) Soluble surface proteins from Helicobacter pylori activate monocytes/macrophages by lipopolysaccharide-independent mechanism. J Clin Invest 87:894–900.  https://doi.org/10.1172/JCI115095 CrossRefPubMedPubMedCentralGoogle Scholar
  93. Mai UE, Perez-Perez GI, Allen JB, Wahl SM, Blaser MJ, Smith PD (1992) Surface proteins from Helicobacter pylori exhibit chemotactic activity for human leukocytes and are present in gastric mucosa. J Exp Med 175:517–525.  https://doi.org/10.1084/jem.175.2.517 CrossRefPubMedGoogle Scholar
  94. Man K, Miasari M, Shi W, Xin A, Henstridge DC, Preston S, Pellegrini M, Belz GT, Smyth GK, Febbraio MA, Nutt SL, Kallies A (2013) The transcription factor IRF4 is essential for TCR affinity–mediated metabolic programming and clonal expansion of T cells. Nat Immunol 14:1155–1165.  https://doi.org/10.1038/ni.2710 CrossRefPubMedGoogle Scholar
  95. Mandell L, Moran AP, Cocchiarella A, Houghton J, Taylor N, Fox JG, Wang TC, Kurt-Jones EA (2004) Intact gram-negative Helicobacter pylori, Helicobacter felis, and Helicobacter hepaticus bacteria activate innate immunity via toll-like receptor 2 but not toll-like receptor 4. Infect Immun 72(11):6446–6454.  https://doi.org/10.1128/IAI.72.11.6446-6454.2004 CrossRefPubMedPubMedCentralGoogle Scholar
  96. Matsumoto Y, Blanchard TG, Drakes ML, Basu M, Redline RW, Levine AD, Czinn SJ (2005) Eradication of Helicobacter pylori and resolution of gastritis in the gastric mucosa of IL-10-deficient mice. Helicobacter 10:407–415.  https://doi.org/10.1111/j.1523-5378.2005.00349.x CrossRefPubMedGoogle Scholar
  97. McGee DJ, George AE, Trainor EA, Horton KE, Hildebrandt E, Testerman TL (2011) Cholesterol enhances Helicobacter pylori resistance to antibiotics and LL-37. Antimicrob Agents Chemother 55:2897–2904.  https://doi.org/10.1128/AAC.00016-11 CrossRefPubMedPubMedCentralGoogle Scholar
  98. McGovern KJ, Blanchard TG, Gutierrez JA, Czinn SJ, Krakowka S, Youngman P (2001) Gamma-Glutamyltransferase is a Helicobacter pylori virulence factor but is not essential for colonization. Infect Immun 69:4168–4173.  https://doi.org/10.1128/IAI.69.6.4168-4173.2001 CrossRefPubMedPubMedCentralGoogle Scholar
  99. Melillo JA, Song L, Bhagat G, Blazquez AB, Plumlee CR, Lee C, Berin C, Reizis B, Schindler C (2010) Dendritic cell (DC)-specific targeting reveals Stat3 as a negative regulator of DC function. J Immunol 184:2638–2645.  https://doi.org/10.4049/jimmunol.0902960 CrossRefPubMedPubMedCentralGoogle Scholar
  100. Molinari M, Salio M, Galli C, Norais N, Rappuoli R, Lanzavecchia A, Montecucco C (1998) Selective inhibition of ii-dependent antigen presentation by Helicobacter pylori toxin VacA. J Exp Med 187:135–140.  https://doi.org/10.1084/jem.187.1.135 CrossRefPubMedPubMedCentralGoogle Scholar
  101. Morey P, Pfannkuch L, Pang E, Boccellato F, Sigal M, Imai-Matsushima A, Dyer V, Koch M, Mollenkopf HJ, Schlaermann P, Meyer TF (2018) Helicobacter pylori depletes cholesterol in gastric glands to prevent interferon gamma signaling and escape the inflammatory iesponse. Gastroenterology 154(5):1391–1404.e9.  https://doi.org/10.1053/j.gastro.2017.12.008 CrossRefPubMedGoogle Scholar
  102. Nagashima H, Iwatani S, Cruz M, Jiménez Abreu JA, Uchida T, Mahachai V, Vilaichone RK, Graham DY, Yamaoka Y (2015) Toll-like receptor 10 in Helicobacter pylori infection. J Infect Dis 212(10):1666–1676.  https://doi.org/10.1093/infdis/jiv270 CrossRefPubMedPubMedCentralGoogle Scholar
  103. Nakayama M, Hisatsune J, Yamasaki E, Nishi Y, Wada A, Kurazono H, Sap J, Yahiro K, Moss J, Hirayama T (2006) Clustering of Helicobacter pylori VacA in lipid rafts, mediated by its receptor, receptor-like protein tyrosine phosphatase beta, is required for intoxication in AZ-521 cells. Infect Immun 74(12):6571–6580.  https://doi.org/10.1128/IAI.00356-06 CrossRefPubMedPubMedCentralGoogle Scholar
  104. Naumann M, Sokolova O, Tegtmeyer N, Backert S (2017) Helicobacter pylori: a paradigm pathogen for subverting host cell signal transmission. Trends Microbiol 25:316–328.  https://doi.org/10.1016/J.TIM.2016.12.004 CrossRefPubMedPubMedCentralGoogle Scholar
  105. Necchi V, Manca R, Ricci V, Solcia E (2009) Evidence for transepithelial dendritic cells in human H. pylori active gastritis. Helicobacter 14:208–222.  https://doi.org/10.1111/j.1523-5378.2009.00679.x CrossRefPubMedGoogle Scholar
  106. Ng GZ, Menheniott TR, Every AL, Stent A, Judd LM, Chionh YT, Dhar P, Komen JC, Giraud AS, Wang TC, McGuckin MA, Sutton P (2016) The MUC1 mucin protects against Helicobacter pylori pathogenesis in mice by regulation of the NLRP3 inflammasome. Gut 65(7):1087–1099.  https://doi.org/10.1136/gutjnl-2014-307175 CrossRefPubMedGoogle Scholar
  107. Nika K, Soldani C, Salek M, Paster W, Gray A, Etzensperger R, Fugger L, Polzella P, Cerundolo V, Dushek O, Höfer T, Viola A, Acuto O (2010) Constitutively active Lck kinase in T cells drives antigen receptor signal transduction. Immunity 32(6):766–777.  https://doi.org/10.1016/j.immuni.2010.05.011 CrossRefPubMedPubMedCentralGoogle Scholar
  108. Obonyo M, Sabet M, Cole SP, Ebmeyer J, Uematsu S, Akira S, Guiney DG (2007) Deficiencies of myeloid differentiation factor 88, toll-like receptor 2 (TLR2), or TLR4 produce specific defects in macrophage cytokine secretion induced by Helicobacter pylori. Infect Immun 75:2408–2414.  https://doi.org/10.1128/IAI.01794-06 CrossRefPubMedPubMedCentralGoogle Scholar
  109. Odenbreit S, Gebert B, Puls J, Fischer W, Haas R (2001) Interaction of Helicobacter pylori with professional phagocytes: role of the cag pathogenicity island and translocation, phosphorylation and processing of CagA. Cell Microbiol 3:21–31.  https://doi.org/10.1046/j.1462-5822.2001.00088.x CrossRefPubMedGoogle Scholar
  110. Oertli M, Sundquist M, Hitzler I, Engler DB, Arnold IC, Reuter S, Maxeiner J, Hansson M, Taube C, Quiding-Järbrink M, Müller A (2012) DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection. J Clin Invest 122:1082–1096.  https://doi.org/10.1172/JCI61029 CrossRefPubMedPubMedCentralGoogle Scholar
  111. Oertli M, Noben M, Engler DB, Semper RP, Reuter S, Maxeiner J, Gerhard M, Taube C, Müller A (2013) Helicobacter pylori γ-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance. Proc Natl Acad Sci U S A 110:3047–3052.  https://doi.org/10.1073/pnas.1211248110 CrossRefPubMedPubMedCentralGoogle Scholar
  112. Oktem-Okullu S, Tiftikci A, Saruc M, Cicek B, Vardareli E, Tozun N, Kocagoz T, Sezerman U, Yavuz AS, Sayi-Yazgan A (2015) Multiplex-PCR-based screening and computational modeling of virulence factors and T-cell mediated immunity in Helicobacter pylori infections for accurate clinical diagnosis. PLoS One 10:e0136212.  https://doi.org/10.1371/journal.pone.0136212 CrossRefPubMedPubMedCentralGoogle Scholar
  113. Ortega-Gómez A, Perretti M, Soehnlein O (2013) Resolution of inflammation: an integrated view. EMBO Mol Med 5(5):661–674.  https://doi.org/10.1002/emmm.201202382 CrossRefPubMedPubMedCentralGoogle Scholar
  114. 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 426:342–349.  https://doi.org/10.1016/j.bbrc.2012.08.080 CrossRefPubMedGoogle Scholar
  115. Pachathundikandi SK, Backert S (2016) Differential expression of interleukin-1β during Helicobacter pylori infection of toll-like receptor 2 (TLR2)- and TLR10-expressing HEK293 cell lines. J Infect Dis 214:166–167.  https://doi.org/10.1093/infdis/jiw154 CrossRefPubMedGoogle Scholar
  116. Pachathundikandi SK, Backert S (2018) Helicobacter pylori controls NLRP3 expression by regulating hsa-miR-223-3p and IL-10 in cultured and primary human immune cells. Innate Immun 24(1):11–23.  https://doi.org/10.1177/1753425917738043 CrossRefPubMedGoogle Scholar
  117. 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.  https://doi.org/10.1371/journal.pone.0019614. Erratum: PLoS One (2015) 10(12):e0144365CrossRefGoogle Scholar
  118. 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.  https://doi.org/10.1155/2015/192420 CrossRefPubMedPubMedCentralGoogle Scholar
  119. Pagliari M, Munari F, Toffoletto M, Lonardi S, Chemello F, Codolo G, Millino C, Della Bella C, Pacchioni B, Vermi W, Fassan M, de Bernard M, Cagnin S (2017) Helicobacter pylori affects the antigen presentation activity of macrophages modulating the expression of the immune receptor CD300E through miR-4270. Front Immunol 8:1288.  https://doi.org/10.3389/fimmu.2017.01288 CrossRefPubMedPubMedCentralGoogle Scholar
  120. Petersen AM, Sorensen K, Blom J, Krogfelt KA (2001) Reduced intracellular survival of Helicobacter pylori vacA mutants in comparison with their wild-types indicates the role of VacA in pathogenesis. FEMS Immunol Med Microbiol 30:103–108.  https://doi.org/10.1111/j.1574-695X.2001.tb01556.x CrossRefPubMedGoogle Scholar
  121. Pfannkuch L, Hurwitz R, Traulsen J, Kosma P, Schmid M, Meyer TF (2018) ADP heptose, a novel pathogen-associated molecular pattern associated with Helicobacter pylori type 4 secretion. bioRxiv.  https://doi.org/10.1101/405951
  122. Posselt G, Backert S, Wessler S (2013) The functional interplay of Helicobacter pylori factors with gastric epithelial cells induces a multi-step process in pathogenesis. Cell Commun Signal 11:77.  https://doi.org/10.1186/1478-811X-11-77 CrossRefPubMedPubMedCentralGoogle Scholar
  123. Quiding-Järbrink M, Raghavan S, Sundquist M (2010) Enhanced M1 macrophage polarization in human Helicobacter pylori-associated atrophic gastritis and in vaccinated mice. PLoS One 5(11):e15018.  https://doi.org/10.1371/journal.pone.0015018 CrossRefPubMedPubMedCentralGoogle Scholar
  124. Rad R, Brenner L, Bauer S, Schwendy S, Layland L, da Costa CP, Reindl W, Dossumbekova A, Friedrich M, Saur D, Wagner H, Schmid RM, Prinz C (2006) CD25+/Foxp3+ T cells regulate gastric inflammation and Helicobacter pylori colonization in vivo. Gastroenterology 131:525–537.  https://doi.org/10.1053/j.gastro.2006.05.001 CrossRefGoogle Scholar
  125. Rad R, Brenner L, Krug A, Voland P, Mages J, Lang R, Schwendy S, Reindl W, Dossumbekova A, Ballhorn W, Wagner H, Schmid RM, Bauer S, Prinz C (2007) Toll-like receptor-dependent activation of antigen-presenting cells affects adaptive immunity to Helicobacter pylori. Gastroenterology 133:150–163.  https://doi.org/10.1053/j.gastro.2007.04.071 CrossRefPubMedGoogle Scholar
  126. Rad R, Ballhorn W, Voland P, Eisenächer 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 136:2247–2257.  https://doi.org/10.1053/j.gastro.2009.02.066 CrossRefPubMedGoogle Scholar
  127. Ramarao N, Gray-Owen SD, Backert S, Meyer TF (2000) Helicobacter pylori inhibits phagocytosis by professional phagocytes involving type IV secretion components. Mol Microbiol 37(6):1389–1404.  https://doi.org/10.1046/j.1365-2958.2000.02089.x CrossRefPubMedGoogle Scholar
  128. Rieder G, Tessier AJ, Qiao XT, Madison B, Gumucio DL, Merchant JL (2005) Helicobacter-induced intestinal metaplasia in the stomach correlates with Elk-1 and serum response factor induction of villin. J Biol Chem 280(6):4906–4912.  https://doi.org/10.1074/jbc.M413399200 CrossRefPubMedGoogle Scholar
  129. Rittig MG, Shaw B, Letley DP, Thomas RJ, Argent RH, Atherton JC (2003) Helicobacter pylori-induced homotypic phagosome fusion in human monocytes is independent of the bacterial vacA and cag status. Cell Microbiol 5:887–899.  https://doi.org/10.1046/j.1462-5822.2003.00328.x CrossRefPubMedGoogle Scholar
  130. Rizzuti D, Ang M, Sokollik C, Wu T, Abdullah M, Greenfield L, Fattouh R, Reardon C, Tang M, Diao J, Schindler C, Cattral M, Jones NL (2015) Helicobacter pylori inhibits dendritic cell maturation via interleukin-10-mediated activation of the signal transducer and activator of transcription 3 pathway. J Innate Immun 7:199–211.  https://doi.org/10.1159/000368232 CrossRefPubMedGoogle Scholar
  131. Roifman CM, Grunebaum E (2013) 35 – Primary T-cell immunodeficiencies. Clin Immunol:437–453.  https://doi.org/10.1016/B978-0-7234-3691-1.00052-0
  132. Satin B, Del Giudice G, Della Bianca V, Dusi S, Laudanna C, Tonello F, Kelleher D, Rappuoli R, Montecucco C, Rossi F (2000) The neutrophil-activating protein (HP-NAP) of Helicobacter pylori is a protective antigen and a major virulence factor. J Exp Med 191:1467–1476.  https://doi.org/10.1084/jem.191.9.1467 CrossRefPubMedPubMedCentralGoogle Scholar
  133. Sayi A, Kohler E, Toller IM, Flavell RA, Müller W, Roers A, Müller A (2011) TLR-2-activated B cells suppress Helicobacter-induced preneoplastic gastric immunopathology by inducing T regulatory-1 cells. J Immunol 186:878–890.  https://doi.org/10.4049/jimmunol.1002269 CrossRefPubMedGoogle Scholar
  134. 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 γ-glutamyl transpeptidase. Gastroenterology 132:1820–1833.  https://doi.org/10.1053/J.GASTRO.2007.02.031 CrossRefPubMedGoogle Scholar
  135. Schwartz JT, Allen LA (2006) Role of urease in megasome formation and Helicobacter pylori survival in macrophages. J Leukoc Biol 79:1214–1225.  https://doi.org/10.1189/jlb.0106030 CrossRefPubMedPubMedCentralGoogle Scholar
  136. 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 3:20–29.  https://doi.org/10.1016/J.CHOM.2007.11.003 CrossRefPubMedGoogle Scholar
  137. Sewald X, Jiménez-Soto L, Haas R (2011) PKC-dependent endocytosis of the Helicobacter pylori vacuolating cytotoxin in primary T lymphocytes. Cell Microbiol 13:482–496.  https://doi.org/10.1111/j.1462-5822.2010.01551.x CrossRefPubMedGoogle Scholar
  138. Shan Y, Lu X, Han Y, Li X, Wang X, Shao C, Wang L, Liu Z, Tang W, Sun Y, Jia J (2015) Helicobacter pylori outer membrane protein 18 (Hp1125) is involved in persistent colonization by evading interferon-γ signaling. Biomed Res Int 2015:571280.  https://doi.org/10.1155/2015/571280 CrossRefPubMedPubMedCentralGoogle Scholar
  139. Shibayama K, Kamachi K, Nagata N, Yagi T, Nada T, Doi Y, Shibata N, Yokoyama K, Yamane K, Kato H, Iinuma Y, Arakawa Y (2003) A novel apoptosis-inducing protein from Helicobacter pylori. Mol Microbiol 47:443–451.  https://doi.org/10.1046/j.1365-2958.2003.03305.x CrossRefPubMedGoogle Scholar
  140. Shibayama K, Wachino J, Arakawa Y, Saidijam M, Rutherford NG, Henderson PJF (2007) Metabolism of glutamine and glutathione via γ-glutamyltranspeptidase and glutamate transport in Helicobacter pylori: possible significance in the pathophysiology of the organism. Mol Microbiol 64:396–406.  https://doi.org/10.1111/j.1365-2958.2007.05661.x CrossRefPubMedGoogle Scholar
  141. Shih SC, Tseng KW, Lin SC, Kao CR, Chou SY, Wang HY, Chang WH, Chu CH, Wang TE, Chien CL (2005) Expression patterns of transforming growth factor-beta and its receptors in gastric mucosa of patients with refractory gastric ulcer. World J Gastroenterol 11(1):136–141.  https://doi.org/10.3748/wjg.v11.i1.136 CrossRefPubMedPubMedCentralGoogle Scholar
  142. Shiu J, Czinn SJ, Kobayashi KS, Sun Y, Blanchard TG (2013) IRAK-M expression limits dendritic cell activation and proinflammatory cytokine production in response to Helicobacter pylori. PLoS One 8(6):e66914.  https://doi.org/10.1371/journal.pone.0066914 CrossRefPubMedPubMedCentralGoogle Scholar
  143. Sierra JC, Hobbs S, Chaturvedi R, Yan F, Wilson KT, Peek RM Jr, Polk DB (2013) Induction of COX-2 expression by Helicobacter pylori is mediated by activation of epidermal growth factor receptor in gastric epithelial cells. Am J Physiol Gastrointest Liver Physiol 305(2):G196–G203.  https://doi.org/10.1152/ajpgi.00495.2012 CrossRefPubMedPubMedCentralGoogle Scholar
  144. Sierra JC, Asim M, Verriere TG, Piazuelo MB, Suarez G, Romero-Gallo J, Delgado AG, Wroblewski LE, Barry DP, Peek RM Jr, Gobert AP, Wilson KT (2018) Epidermal growth factor receptor inhibition downregulates Helicobacter pylori-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis. Gut 67(7):1247–1260.  https://doi.org/10.1136/gutjnl-2016-312888 CrossRefPubMedGoogle Scholar
  145. Singh A, Hodgson N, Yan M, Joo J, Gu L, Sang H, Gregory-Bryson E, Wood WG, Ni Y, Smith K, Jackson SH, Coleman WG (2012) Screening Helicobacter pylori genes induced during infection of mouse stomachs. World J Gastroenterol 18:4323–4334.  https://doi.org/10.3748/wjg.v18.i32.4323 CrossRefPubMedPubMedCentralGoogle Scholar
  146. Smith-Garvin JE, Koretzky GA, Jordan MS (2009) T cell activation. Annu Rev Immunol 27:591–619.  https://doi.org/10.1146/annurev.immunol.021908.132706 CrossRefPubMedPubMedCentralGoogle Scholar
  147. Sommer F, Faller G, Röllinghoff M, Kirchner T, Mak TW, Lohoff M (2001) Lack of gastritis and of an adaptive immune response in interferon regulatory factor-1-deficient mice infected with Helicobacter pylori. Eur J Immunol 31:396–402. https://doi.org/10.1002/1521-4141(200102)31:2<396::AID-IMMU396>3.0.CO;2-YCrossRefPubMedGoogle Scholar
  148. Song JY, Choi YJ, Kim JM, Kim YR, Jo JS, Park JS, Park HJ, Song YG, Lee KH, Kang HL, Baik SC, Youn HS, Cho MJ, Rhee KH, Lee WK (2011) Purification and characterization of Helicobacter pylori γ-glutamyltranspeptidase. J Bacteriol Virol 41:255–265.  https://doi.org/10.4167/jbv.2011.41.4.255 CrossRefGoogle Scholar
  149. Stein SC, Faber E, Bats SH, Murillo T, Speidel Y, Coombs N, Josenhans C (2017) Helicobacter pylori modulates host cell responses by CagT4SS-dependent translocation of an intermediate metabolite of LPS inner core heptose biosynthesis. PLoS Pathog 13(7):e1006514.  https://doi.org/10.1371/journal.ppat.1006514 CrossRefPubMedPubMedCentralGoogle Scholar
  150. Sugimoto MA, Sousa LP, Pinho V, Perretti M, Teixeira MM (2016) Resolution of inflammation: what controls its onset? Front Immunol 7:160.  https://doi.org/10.3389/fimmu.2016.00160 CrossRefPubMedPubMedCentralGoogle Scholar
  151. Sun X, Zhang M, El-Zataari M, Owyang SY, Eaton KA, Liu M, Chang YM, Zou W, Kao JY (2013) TLR2 mediates Helicobacter pylori-induced tolerogenic immune response in mice. PLoS One 8:e74595.  https://doi.org/10.1371/journal.pone.0074595 CrossRefPubMedPubMedCentralGoogle Scholar
  152. 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 U S A 101:7727–7732.  https://doi.org/10.1073/pnas.0401528101 CrossRefPubMedPubMedCentralGoogle Scholar
  153. Suzuki N, Murata-Kamiya N, Yanagiya K, Suda W, Hattori M, Kanda H, Bingo A, Fujii Y, Maeda S, Koike K, Hatakeyama M (2015) Mutual reinforcement of inflammation and carcinogenesis by the Helicobacter pylori CagA oncoprotein. Sci Rep 5:10024.  https://doi.org/10.1038/srep10024 CrossRefPubMedPubMedCentralGoogle Scholar
  154. Takabayashi H, Shinohara M, Mao M, Phaosawasdi P, El-Zaatari M, Zhang M, Ji T, Eaton KA, Dang D, Kao J, Todisco A (2014) Anti-inflammatory activity of bone morphogenetic protein signaling pathways in stomachs of mice. Gastroenterology 147(2):396–406.e7.  https://doi.org/10.1053/j.gastro.2014.04.015 CrossRefPubMedPubMedCentralGoogle Scholar
  155. Takeshima E, Tomimori K, Takamatsu R, Ishikawa C, Kinjo F, Hirayama T, Fujita J, Mori N (2009) Helicobacter pylori VacA activates NF-κB in T cells via the classical but not alternative pathway. Helicobacter 14:271–279.  https://doi.org/10.1111/j.1523-5378.2009.00683.x CrossRefPubMedGoogle Scholar
  156. Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140(6):805–820.  https://doi.org/10.1016/j.cell.2010.01.022 CrossRefPubMedGoogle Scholar
  157. 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 498:35–42.  https://doi.org/10.1016/J.ABB.2010.03.021 CrossRefPubMedGoogle Scholar
  158. Tang B, Li N, Gu J, Zhuang Y, Li Q, Wang HG, Fang Y, Yu B, Zhang JY, Xie QH, Chen L, Jiang XJ, Xiao B, Zou QM, Mao XH (2012) Compromised autophagy by MIR30B benefits the intracellular survival of Helicobacter pylori. Autophagy 8:1045–1057.  https://doi.org/10.4161/auto.20159 CrossRefPubMedPubMedCentralGoogle Scholar
  159. Tegtmeyer N, Wessler S, Backert S (2011) Role of the cag-pathogenicity island encoded type IV secretion system in Helicobacter pylori pathogenesis. FEBS J 278:1190–1202.  https://doi.org/10.1111/j.1742-4658.2011.08035.x CrossRefPubMedPubMedCentralGoogle Scholar
  160. Terebiznik MR, Vazquez CL, Torbicki K, Banks D, Wang T, Hong W, Blanke SR, Colombo MI, Jones NL (2006) Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells. Infect Immun 74:6599–6614.  https://doi.org/10.1128/IAI.01085-06 CrossRefPubMedPubMedCentralGoogle Scholar
  161. Tonello F, Dundon WG, Satin B, Molinari M, Tognon G, Grandi G, Del Giudice G, Rappuoli R, Montecucco C (1999) The Helicobacter pylori neutrophil-activating protein is an iron-binding protein with dodecameric structure. Mol Microbiol 34:238–246.  https://doi.org/10.1046/j.1365-2958.1999.01584.x CrossRefPubMedGoogle Scholar
  162. Varga MG, Shaffer CL, Sierra JC, Suarez G, Piazuelo MB, Whitaker ME, Romero-Gallo J, Krishna US, Delgado A, Gomez MA, Good JA, Almqvist F, Skaar EP, Correa P, Wilson KT, Hadjifrangiskou M, Peek RM (2016) Pathogenic Helicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system. Oncogene 35:6262–6269.  https://doi.org/10.1038/onc.2016.158 CrossRefPubMedPubMedCentralGoogle Scholar
  163. Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, Athman R, Mémet S, Huerre MR, Coyle AJ, DiStefano PS, Sansonetti PJ, Labigne A, Bertin J, Philpott DJ, Ferrero RL (2004) Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol 5:1166–1174.  https://doi.org/10.1038/ni1131 CrossRefPubMedGoogle Scholar
  164. Wagner S, Beil W, Westermann J, Logan RP, Bock CT, Trautwein C, Bleck JS, Manns MP (1997) Regulation of gastric epithelial cell growth by Helicobacter pylori: evidence for a major role of apoptosis. Gastroenterology 113:1836–1847CrossRefGoogle Scholar
  165. Wang G, Maier RJ (2015) A novel DNA-binding protein plays an important role in Helicobacter pylori stress tolerance and survival in the host. J Bacteriol 197:973–982.  https://doi.org/10.1128/JB.02489-14 CrossRefPubMedPubMedCentralGoogle Scholar
  166. 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 167:926–934.  https://doi.org/10.4049/JIMMUNOL.167.2.926 CrossRefPubMedGoogle Scholar
  167. Wang G, Hong Y, Olczak A, Maier SE, Maier RJ (2006) Dual roles of Helicobacter pylori NapA in inducing and combating oxidative stress. Infect Immun 74:6839–6846.  https://doi.org/10.1128/IAI.00991-06 CrossRefPubMedPubMedCentralGoogle Scholar
  168. Wang YH, Wu JJ, Lei HY (2009) When Helicobacter pylori invades and replicates in the cells. Autophagy 5(4):540–542.  https://doi.org/10.4161/auto.5.4.8167 CrossRefPubMedGoogle Scholar
  169. Wang YH, Gorvel JP, Chu YT, Wu JJ, Lei HY (2010) Helicobacter pylori impairs murine dendritic cell responses to infection. PLoS One 5:e10844.  https://doi.org/10.1371/journal.pone.0010844 CrossRefPubMedPubMedCentralGoogle Scholar
  170. Wang HJ, Cheng WC, Cheng HH, Lai CH, Wang WC (2012) Helicobacter pylori cholesteryl glucosides interfere with host membrane phase and affect type IV secretion system function during infection in AGS cells. Mol Microbiol 83:67–84.  https://doi.org/10.1111/j.1365-2958.2011.07910.x CrossRefPubMedGoogle Scholar
  171. White JR, Winter JA, Robinson K (2015) Differential inflammatory response to Helicobacter pylori infection: etiology and clinical outcomes. J Inflamm Res 8:137–147.  https://doi.org/10.2147/JIR.S64888 CrossRefPubMedPubMedCentralGoogle Scholar
  172. Wroblewski LE, Peek RM, Wilson KT, Wilson KT (2010) Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev 23:713–739.  https://doi.org/10.1128/CMR.00011-10 CrossRefGoogle Scholar
  173. Wunder C, Churin Y, Winau F, Warnecke D, Vieth M, Lindner B, Zähringer U, Mollenkopf HJ, Heinz E, Meyer TF (2006) Cholesterol glucosylation promotes immune evasion by Helicobacter pylori. Nat Med 12:1030–1038.  https://doi.org/10.1038/nm1480 CrossRefPubMedGoogle Scholar
  174. 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 17:51–61.  https://doi.org/10.1111/cmi.12335 CrossRefPubMedGoogle Scholar
  175. Yang Y, Mayo KH, Daly TJ, Barry JK, La Rosa GJ (1994) Subunit association and structural analysis of platelet basic protein and related proteins investigated by 1H NMR spectroscopy and circular dichroism. J Biol Chem 269:20110–20118PubMedGoogle Scholar
  176. Yao S, Buzo BF, Pham D, Jiang L, Taparowsky EJ, Kaplan MH, Sun J (2013) Interferon regulatory factor 4 sustains CD8(+) T cell expansion and effector differentiation. Immunity 39:833–845.  https://doi.org/10.1016/j.immuni.2013.10.007 CrossRefPubMedGoogle Scholar
  177. Yaqoob P, Calder PC (1997) Glutamine requirement of proliferating T lymphocytes. Nutrition 13:646–651.  https://doi.org/10.1016/S0899-9007(97)83008-0 CrossRefPubMedGoogle Scholar
  178. Yokoyama K, Higashi H, Ishikawa S, Fujii Y, Kondo S, Kato H, Azuma T, Wada A, Hirayama T, Aburatani H, Hatakeyama M (2005) Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells. Proc Natl Acad Sci U S A 102:9661–9666.  https://doi.org/10.1073/pnas.0502529102 CrossRefPubMedPubMedCentralGoogle Scholar
  179. Zanotti G, Papinutto E, Dundon W, Battistutta R, Seveso M, Giudice G, Rappuoli R, Montecucco C (2002) Structure of the neutrophil-activating protein from Helicobacter pylori. J Mol Biol 323:125–130.  https://doi.org/10.1016/S0022-2836(02)00879-3 CrossRefPubMedGoogle Scholar
  180. Zeaiter Z, Cohen D, Müsch A, Bagnoli F, Covacci A, Stein M (2008) Analysis of detergent-resistant membranes of Helicobacter pylori infected gastric adenocarcinoma cells reveals a role for MARK2/Par1b in CagA-mediated disruption of cellular polarity. Cell Microbiol 10:781–794.  https://doi.org/10.1111/j.1462-5822.2007.01084.x CrossRefPubMedGoogle Scholar
  181. Zeaiter Z, Diaz H, Stein M, Huynh HQ (2011) Helicobacter pylori induces expression and secretion of oncostatin M in macrophages in vitro. Dig Dis Sci 56:689–697.  https://doi.org/10.1007/s10620-010-1341-z CrossRefPubMedGoogle Scholar
  182. Zhang B, Chikuma S, Hori S, Fagarasan S, Honjo T (2016) Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model. Proc Natl Acad Sci U S A 113:8490–8495.  https://doi.org/10.1073/pnas.1608873113 CrossRefPubMedPubMedCentralGoogle Scholar
  183. Zhao Y, Yokota K, Ayada K, Yamamoto Y, Okada T, Shen L, Oguma K (2007) Helicobacter pylori heat-shock protein 60 induces interleukin-8 via a toll-like receptor (TLR)2 and mitogen-activated protein (MAP) kinase pathway in human monocytes. J Med Microbiol 56:154–164.  https://doi.org/10.1099/jmm.0.46882-0 CrossRefPubMedGoogle Scholar
  184. Zheng Y, Zha Y, Gajewski TF (2008) Molecular regulation of T-cell anergy. EMBO Rep 9:50–55.  https://doi.org/10.1038/sj.embor.7401138 CrossRefPubMedPubMedCentralGoogle Scholar
  185. Zhou P, She Y, Dong N, Li P, He H, Borio A, Wu Q, Lu S, Ding X, Cao Y, Xu Y, Gao W, Dong M, Ding J, Wang DC, Zamyatina A, Shao F (2018) Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose. Nature 561:122–126.  https://doi.org/10.1038/s41586-018-0433-3 CrossRefPubMedGoogle Scholar
  186. Zimmermann S, Pfannkuch L, Al-Zeer MA, Bartfeld S, Koch M, Liu J, Rechner C, Soerensen M, Sokolova O, Zamyatina A, Kosma P, Mäurer AP, Glowinski F, Pleissner KP, Schmid M, Brinkmann V, Karlas A, Naumann M, Rother M, Machuy N, Meyer TF (2017) ALPK1- and TIFA-dependent innate immune response triggered by the Helicobacter pylori type IV secretion system. Cell Rep 20(10):2384–2395.  https://doi.org/10.1016/j.celrep.2017.08.039 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Nicole Blaser
    • 1
  • Steffen Backert
    • 1
  • Suneesh Kumar Pachathundikandi
    • 1
    Email author
  1. 1.Department of Biology, Institute for MicrobiologyFriedrich Alexander University Erlangen-NurembergErlangenGermany

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