Importance of Toll-like Receptors in Pro-inflammatory and Anti-inflammatory Responses by Helicobacter pylori Infection

  • Hiroyuki Nagashima
  • Yoshio YamaokaEmail author
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 421)


Infectious diseases have been paramount among the threats to human health and survival throughout evolutionary history. Bacterial cell-surface molecules are key factors in the microorganism–host crosstalk, as they can interact with host pattern-recognition receptors (PRRs) of the gastrointestinal mucosa. The best-studied PRRs are toll-like receptors (TLRs). Because TLRs play an important key role in host defense, they have received increasing interest in the evolutionary and population genetics literature, and their variation represents a potential target of adaptive evolution. Helicobacter pylori is one of the commensal bacteria in our body and can have pathogenic properties in a subset of infected people. The history of H. pylori research indicated that humans and bacteria co-evolved during evolution. A genome-wide association study (GWAS) has opened the way for investigating the genomic evolution of bacterial pathogens during the colonization and infection of humans. Recent GWAS research emphasized the importance of TLRs, especially TLR10 during pathogenesis in H. pylori infection. We demonstrated that TLR10, whose ligand was unknown for a long time, can recognize H. pylori LPS. Our results of H. pylori research suggest that TLR10 might play an important role to also recognize other commensal bacteria. In this review, we discuss the importance of TLRs in pro-inflammatory and anti-inflammatory responses by H. pylori infection. Especially, we highlight the TLR10 interaction with H. pylori infection, providing new insights about TLR10 signaling.


Toll-like receptor TLR10 H. pylori LPS Innate immunity Microbiome 



The author acknowledges support from the National Institute of Diabetes and Digestive and Kidney Diseases of the United States (grant DK62813); the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (grant 16H05191); and from the Japan Society for the Promotion of Science (Core-to-Core Program).


  1. Alcais A, Abel L, Casanova JL (2009) Human genetics of infectious diseases: between proof of principle and paradigm. J Clin Invest 119:2506–2514. Scholar
  2. Alexander C, Rietschel ET (2001) Bacterial lipopolysaccharides and innate immunity. J Endotoxin Res 7:167–202Google Scholar
  3. 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 102:9247–9252.
  4. Arnold IC, Dehzad N, Reuter S, Martin H, Becher B, Taube C, Muller A (2011) Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells. J Clin Invest 121:3088–3093. Scholar
  5. Bach JF (2018) The hygiene hypothesis in autoimmunity: the role of pathogens and commensals. Nat Rev Immunol 18:105–120. Scholar
  6. Backhed F et al (2003) Gastric mucosal recognition of Helicobacter pylori is independent of Toll-like receptor 4. J Infect Dis 187:829–836.
  7. Backert S, Naumann M (2010) What a disorder: proinflammatory signaling pathways induced by Helicobacter pylori. Trends Microbiol 18:479–486. Scholar
  8. Backert S, Tegtmeyer N, Fischer W (2015) Composition, structure and function of the Helicobacter pylori cag pathogenicity island encoded type IV secretion system. Future Microbiol 10:955–965. Scholar
  9. Barreiro LB, Quintana-Murci L (2010) From evolutionary genetics to human immunology: how selection shapes host defence genes. Nat Rev Genet 11:17–30. Scholar
  10. Barreiro LB et al (2009) Evolutionary dynamics of human toll-like receptors and their different contributions to host defense. PLoS Genet 5:e1000562. Scholar
  11. Beutler B et al (2006) Genetic analysis of host resistance: toll-like receptor signaling and immunity at large. Ann Rev Immunol 24:353–389. Scholar
  12. Blaser MJ, Kirschner D (1999) Dynamics of Helicobacter pylori colonization in relation to the host response. Proc Natl Acad Sci USA 96:8359–8364Google Scholar
  13. Casanova JL, Abel L, Quintana-Murci L (2011) Human TLRs and IL-1Rs in host defense: natural insights from evolutionary, epidemiological, and clinical genetics. Annu Rev Immunol 29:447–491. Scholar
  14. Censini S et al (1996) Cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Nat Acad Sci USA 93:14648–14653CrossRefGoogle Scholar
  15. Chapman SJ, Hill AV (2012) Human genetic susceptibility to infectious disease. Nat Rev Genet 13:175–188. Scholar
  16. Chau TA et al (2009) Toll-like receptor 2 ligands on the staphylococcal cell wall downregulate superantigen-induced T cell activation and prevent toxic shock syndrome. Nat Med 15:641–648. Scholar
  17. Chochi K et al (2008) Helicobacter pylori augments growth of gastric cancers via the lipopolysaccharide-toll-like receptor 4 pathway whereas its lipopolysaccharide attenuates antitumor activities of human mononuclear cells. Clin Cancer Res: An Official J Am Assoc Cancer Res 14:2909–2917. Scholar
  18. Chuang T, Ulevitch RJ (2001) Identification of hTLR10: a novel human toll-like receptor preferentially expressed in immune cells. Biochimica et biophysica acta 1518:157–161CrossRefGoogle Scholar
  19. 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:e1002454. Scholar
  20. Daley D et al (2009) Analyses of associations with asthma in four asthma population samples from Canada and Australia. Hum Genet 125:445–459. Scholar
  21. Dannemann M, Andres AM, Kelso J (2016) Introgression of Neandertal- and Denisovan-like haplotypes contributes to adaptive variation in human toll-like receptors. Am J Hum Genet 98:22–33. Scholar
  22. Deschamps M et al (2016) Genomic signatures of selective pressures and introgression from archaic hominins at human innate immunity genes. Am J Hum Genet 98:5–21. Scholar
  23. Enard D, Depaulis F, Roest Crollius H (2010) Human and non-human primate genomes share hotspots of positive selection. PLoS Genet 6:e1000840. Scholar
  24. Erridge C, Pridmore A, Eley A, Stewart J, Poxton IR (2004) Lipopolysaccharides of Bacteroides fragilis, Chlamydia trachomatis and Pseudomonas aeruginosa signal via toll-like receptor 2. J Med Microbiol 53:735–740. Scholar
  25. Ferrer-Admetlla A et al (2008) Balancing selection is the main force shaping the evolution of innate immunity genes. J Immunol 181:1315–1322CrossRefGoogle Scholar
  26. Gewirtz AT, Yu Y, Krishna US, Israel DA, Lyons SL, Peek RM Jr (2004) Helicobacter pylori flagellin evades toll-like receptor 5-mediated innate immunity. J Infect Dis 189:1914–1920. Scholar
  27. Hankins JV, Madsen JA, Giles DK, Brodbelt JS, Trent MS (2012) Amino acid addition to Vibrio cholerae LPS establishes a link between surface remodeling in gram-positive and gram-negative bacteria. Proc Natl Acad Sci USA 109:8722–8727. Scholar
  28. Henmyr V, Carlberg D, Manderstedt E, Lind-Hallden C, Sall T, Cardell LO, Hallden C (2017) Genetic variation of the toll-like receptors in a Swedish allergic rhinitis case population. BMC Med Genet 18:18. Scholar
  29. Hinds DA et al (2013) A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci. Nat Genet 45:907–911. Scholar
  30. Horng T, Barton GM, Flavell RA, Medzhitov R (2002) The adaptor molecule TIRAP provides signalling specificity for toll-like receptors. Nature 420:329–333. Scholar
  31. Huang YH, Temperley ND, Ren LM, Smith J, Li N, Burt DW (2011) Molecular evolution of the vertebrate TLR1 gene family—a complex history of gene duplication, gene conversion, positive selection and co-evolution. BMC Evol Biol 11:149. Scholar
  32. Hughes AL, Piontkivska H (2008) Functional diversification of the toll-like receptor gene family. Immunogenetics 60:249–256.
  33. Innan H, Kondrashov F (2010) The evolution of gene duplications: classifying and distinguishing between models. Nat Rev Genet 11:97–108. Scholar
  34. Ishihara S et al (2004) Essential role of MD-2 in TLR4-dependent signaling during Helicobacter pylori-associated gastritis. J Immunol 173:1406–1416CrossRefGoogle Scholar
  35. Jann OC, Werling D, Chang JS, Haig D, Glass EJ (2008) Molecular evolution of bovine Toll-like receptor 2 suggests substitutions of functional relevance. BMC Evol Biol 8:288.
  36. Jiang S, Li X, Hess NJ, Guan Y, Tapping RI (2016) TLR10 Is a Negative Regulator of Both MyD88-Dependent and -Independent TLR Signaling. J Immunol 196:3834–3841. Scholar
  37. Jin MS et al (2007) Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 130:1071–1082.
  38. Jin MS, Lee JO (2008) Structures of the toll-like receptor family and its ligand complexes. Immunity 29:182–191.
  39. Kawahara T, Teshima S, Oka A, Sugiyama T, Kishi K, Rokutan K (2001) Type I Helicobacter pylori lipopolysaccharide stimulates toll-like receptor 4 and activates mitogen oxidase 1 in gastric pit cells. Infect Immun 69:4382–4389. Scholar
  40. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373–384.
  41. Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–650. Scholar
  42. Kim HM et al (2007) Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist. Eritoran Cell 130:906–917. Scholar
  43. Kim DJ, Park JH, Franchi L, Backert S, Nunez G (2013) The Cag pathogenicity island and interaction between TLR2/NOD2 and NLRP3 regulate IL-1beta production in Helicobacter pylori infected dendritic cells. Eur J Immunol 43:2650–2658. Scholar
  44. 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. Scholar
  45. Kodaman N et al (2014a) Human and Helicobacter pylori coevolution shapes the risk of gastric disease. Proc Natl Acad Sci USA 111:1455–1460. Scholar
  46. Kodaman N, Sobota RS, Mera R, Schneider BG, Williams SM (2014b) Disrupted human-pathogen co-evolution: a model for disease. Front Genet 5:290. Scholar
  47. Kormann MS et al (2008) Toll-like receptor heterodimer variants protect from childhood asthma. J Allergy Clin Immunol 122:86–92, e81–88.
  48. Kumar Pachathundikandi S, Brandt S, Madassery J, Backert S (2011) Induction of TLR-2 and TLR-5 expression by Helicobacter pylori switches cagPAI-dependent signalling leading to the secretion of IL-8 and TNF-α. PLoS ONE 6:e19614. Scholar
  49. Laayouni H et al (2014) Convergent evolution in European and Rroma populations reveals pressure exerted by plague on Toll-like receptors. Proc Natl Acad Sci USA 111:2668–2673.
  50. Lauhkonen E et al (2016) Gene polymorphism of toll-like receptors and lung function at five to seven years of age after infant bronchiolitis. PloS one 11:e0146526. Scholar
  51. Lee SM et al (2014) Toll-like receptor 10 is involved in induction of innate immune responses to influenza virus infection. Proc Nat Acad Sci USA 111(10):3793–3798. Scholar
  52. Long M, Betran E, Thornton K, Wang W (2003) The origin of new genes: glimpses from the young and old. Nat Rev Genet 4:865–875. Scholar
  53. Maeda S et al (2001) Distinct mechanism of Helicobacter pylori-mediated NF-kappa B activation between gastric cancer cells and monocytic cells. J Biol Chem 276:44856–44864. Scholar
  54. Mailaparambil B, Krueger M, Heinze J, Forster J, Heinzmann A (2008) Polymorphisms of toll like receptors in the genetics of severe RSV associated diseases. Dis Markers 25:59–65CrossRefGoogle Scholar
  55. Mandell L et al (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 72:6446–6454
  56. Mathieson I et al (2015) Genome-wide patterns of selection in 230 ancient. Eurasians Nat 528:499–503. Scholar
  57. Matsushima N, Tanaka T, Enkhbayar P, Mikami T, Taga M, Yamada K, Kuroki Y (2007) Comparative sequence analysis of leucine-rich repeats (LRRs) within vertebrate toll-like receptors. BMC Genomics 8:124. Scholar
  58. Mayerle J et al (2013) Identification of genetic loci associated with Helicobacter pylori serologic status. JAMA, J Am Med Assoc 309:1912–1920. Scholar
  59. Montminy SW et al (2006) Virulence factors of Yersinia pestis are overcome by a strong lipopolysaccharide response. Nat Immunol 7:1066–1073. Scholar
  60. Morath S, Stadelmaier A, Geyer A, Schmidt RR, Hartung T (2002) Synthetic lipoteichoic acid from Staphylococcus aureus is a potent stimulus of cytokine release. J Exp Med 195:1635–1640CrossRefGoogle Scholar
  61. Morgan AR, Lam WJ, Han DY, Fraser AG, Ferguson LR (2012) Genetic variation within TLR10 is associated with Crohn’s disease in a New Zealand population. Hum Immunol 73:416–420. Scholar
  62. Mukherjee S, Sarkar-Roy N, Wagener DK, Majumder PP (2009) Signatures of natural selection are not uniform across genes of innate immune system, but purifying selection is the dominant signature. Proc Nat Acad Sci USA 106:7073–7078. Scholar
  63. Nagashima H et al (2015) Toll-like receptor 10 in Helicobacter pylori infection. The Journal of Infectious Diseases. 212:1666. Scholar
  64. 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. Scholar
  65. Needham BD, Trent MS (2013) Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis. Nat Rev Microbiol 11:467–481. Scholar
  66. Oosting M et al (2014) Human TLR10 is an anti-inflammatory pattern-recognition receptor. Proc Nat Acad Sci USA 111:E4478–E4484. Scholar
  67. 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. Scholar
  68. 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 24:11–23. Scholar
  69. Pachathundikandi SK, Tegtmeyer N, Backert S (2013) Signal transduction of Helicobacter pylori during interaction with host cell protein receptors of epithelial and immune cells. Gut Microbes 4:454–474. Scholar
  70. 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. Scholar
  71. 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. Scholar
  72. Quintana-Murci L, Clark AG (2013) Population genetic tools for dissecting innate immunity in humans. Nat Rev Immunol 13:280–293. Scholar
  73. Rad R et al (2009) Extracellular and intracellular pattern recognition receptors cooperate in the recognition of Helicobacter pylori. Gastroenterology 136:2247–2257. Scholar
  74. Raetz CR, Whitfield C (2002) Lipopolysaccharide endotoxins. Ann Rev Biochem 71:635–700. Scholar
  75. Raetz CR, Reynolds CM, Trent MS, Bishop RE (2007) Lipid A modification systems in gram-negative bacteria. Annu Rev Biochem 76:295–329. Scholar
  76. Ram MR et al (2015) Polymorphisms at locus 4p14 of toll-like receptors TLR-1 and TLR-10 confer susceptibility to gastric carcinoma in Helicobacter pylori infection. PloS One 10:e0141865. Scholar
  77. Rast JP, Smith LC, Loza-Coll M, Hibino T, Litman GW (2006) Genomic insights into the immune system of the sea urchin. Science 314:952–956. Scholar
  78. Regan T, Nally K, Carmody R, Houston A, Shanahan F, Macsharry J, Brint E (2013) Identification of TLR10 as a key mediator of the inflammatory response to Listeria monocytogenes in intestinal epithelial cells and macrophages. Journal of immunology 191:6084–6092. Scholar
  79. Renkonen J, Joenvaara S, Parviainen V, Mattila P, Renkonen R (2010) Network analysis of single nucleotide polymorphisms in asthma. J Asthma Allergy 3:177–186. Scholar
  80. Roach JC et al (2005) The evolution of vertebrate toll-like receptors. Proc Natl Acad Sci USA 102:9577–9582. Scholar
  81. Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, Mazmanian SK (2011) The toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332:974–977. Scholar
  82. Sassi N, Paul C, Martin A, Bettaieb A, Jeannin JF (2010) Lipid A-induced responses in vivo. Adv Exp Med Biol 667:69–80. Scholar
  83. Sayi A, Kohler E, Toller IM, Flavell RA, Muller W, Roers A, Muller A (2011) TLR-2-activated B cells suppress Helicobacter-induced preneoplastic gastric immunopathology by inducing T regulatory-1 cells. J Immunol 186:878–890. Scholar
  84. Schnare M, Barton GM, Holt AC, Takeda K, Akira S, Medzhitov R (2001) Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2:947–950. Scholar
  85. Smith MF Jr et al (2003) Toll-like receptor (TLR) 2 and TLR5, but not TLR4, are required for Helicobacter pylori-induced NF-kappa B activation and chemokine expression by epithelial cells. J Biol Chem 278:32552–32560. Scholar
  86. Smith SM et al (2011) Tribbles 3: a novel regulator of TLR2-mediated signaling in response to Helicobacter pylori lipopolysaccharide. J Immunol 186:2462–2471. Scholar
  87. Stappers MH et al (2015) Genetic variation in TLR10, an inhibitory toll-like receptor, influences susceptibility to complicated skin and skin structure infections. J Infect Dis 212:1491–1499. Scholar
  88. Steimle A, Autenrieth IB, Frick JS (2016) Structure and function: lipid A modifications in commensals and pathogens. Int J Med Microbiol IJMM 306:290–301. Scholar
  89. Sung H, Camargo MC, Yu K, Weinstein SJ, Morgan DR, Albanes D, Rabkin CS (2015) Association of 4p14 TLR locus with antibodies to Helicobacter pylori. Genes Immun 16(8):567–570. Scholar
  90. Takenaka R et al (2004) Helicobacter pylori heat-shock protein 60 induces inflammatory responses through the toll-like receptor-triggered pathway in cultured human gastric epithelial cells. Microbiology 150:3913–3922. Scholar
  91. Tan Y, Zanoni I, Cullen TW, Goodman AL, Kagan JC (2015) Mechanisms of toll-like receptor 4 endocytosis reveal a common immune-evasion strategy used by pathogenic and commensal bacteria. Immunity 43:909–922. Scholar
  92. Tang FB et al (2015) Toll-like receptor 1 and 10 polymorphisms, Helicobacter pylori susceptibility and risk of gastric lesions in a high-risk Chinese population. Infect Genet Evol 31:263–269. Scholar
  93. Tongtawee T, Bartpho T, Wattanawongdon W, Dechsukhum C, Leeanansaksiri W, Matrakool L, Panpimanmas S (2017) Role of toll-like receptor 10 gene polymorphism and gastric mucosal pattern in patients with chronic gastritis. Turk J Gastroenterol 28:243–247. Scholar
  94. Tongtawee T et al (2018) Genetic polymorphisms in TLR1, TLR2, TLR4, and TLR10 of Helicobacter pylori-associated gastritis: a prospective cross-sectional study in Thailand. Eur J Cancer Prev 27:118–123. Scholar
  95. Torok AM, Bouton AH, Goldberg JB (2005) Helicobacter pylori induces interleukin-8 secretion by toll-like receptor 2- and toll-like receptor 5-dependent and -independent pathways. Infect Immun 73:1523–1531. Scholar
  96. Triantafilou M, Uddin A, Maher S, Charalambous N, Hamm TS, Alsumaiti A, Triantafilou K (2007) Anthrax toxin evades Toll-like receptor recognition, whereas its cell wall components trigger activation via TLR2/6 heterodimers. Cell Microbiol 9:2880–2892.
  97. Varga MG et al (2016) Pathogenic Helicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system. Oncogene 35:6262–6269. Scholar
  98. Wang Y et al (2018) Polymorphisms in toll-Like receptor 10 and tuberculosis susceptibility: evidence from three independent series. Front Immunol 9:309. Scholar
  99. Werts C et al (2001) Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism. Nat Immunol 2:346–352. Scholar
  100. Xu TJ, Wang YJ, Li JR, Shu C, Han JJ, Chu Q (2016) Comparative genomic evidence for duplication of TLR1 subfamily and miiuy croaker TLR1 perceives LPS stimulation via MyD88 and TIRAP. Fish Shellfish Immun 56:336–348. Scholar
  101. Yamamoto M et al (2002) Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420:324–329. Scholar
  102. Yang RB et al (1998) Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling. Nature 395:284–288. Scholar
  103. 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 51:140–148. Scholar
  104. Zhang XS, Tegtmeyer N, Traube L, Jindal S, Perez-Perez G, Sticht H, Backert S, Blaser MJ (2015) A specific A/T polymorphism in western tyrosine phosphorylation B-motifs regulates Helicobacter pylori CagA epithelial cell interaction. PloS Pathog 11:e1004621. Scholar
  105. Zhou H, Gu J, Lamont SJ, Gu X (2007) Evolutionary analysis for functional divergence of the toll-like receptor gene family and altered functional constraints. J Mol Evol 65:119–123. Scholar

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Authors and Affiliations

  1. 1.Department of GastroenterologyHokkaido Cancer CenterSapporoJapan
  2. 2.Department of Environmental and Preventive Medicine, Faculty of MedicineOita UniversityYufu-City, OitaJapan
  3. 3.Department of Gastroenterology and HepatologyBaylor College of MedicineHoustonUSA

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