Abstract
The ability of Helicobacter pylori to persist lifelong in the human gastric mucosa is a striking phenomenon. It is even more surprising since infection is typically associated with a vivid inflammatory response. Recent studies revealed the mechanism by which this pathogen inhibits the epithelial responses to IFN-γ and other central inflammatory cytokines in order to abolish an effective antimicrobial defense. The mechanism is based on the modification and depletion of cholesterol by the pathogen’s cholesterol-α-glucosyltransferase. It abrogates the assembly of numerous cytokine receptors due to the reduction of lipid rafts. Particularly, the receptors for IFN-γ, IL-22, and IL-6 then fail to assemble properly and to activate JAK/STAT signaling. Consequently, cholesterol depletion prevents the release of antimicrobial peptides, including the highly effective β-defensin-3. Intriguingly, the inhibition is spatially restricted to heavily infected cells, while the surrounding epithelium continues to respond normally to cytokine stimulation, thus providing a platform of the intense inflammation typically observed in H. pylori infections. It appears that pathogen and host establish a homeostatic balance between tightly colonized and rather inflamed sites. This homeostasis is influenced by the levels of available cholesterol, which potentially exacerbate H. pylori-induced inflammation. The observed blockage of epithelial effector mechanisms by H. pylori constitutes a convincing explanation for the previous failures of T-cell-based vaccination against H. pylori, since infected epithelial cells remain inert upon stimulation by effector cytokines. Moreover, the mechanism provides a rationale for the carcinogenic action of this pathogen in that persistent infection and chronic inflammation represent a pro-carcinogenic environment. Thus, cholesterol-α-glucosyltransferase has been revealed as a central pathogenesis determinant of H. pylori.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Aebischer T, Meyer TF, Andersen LP (2010) Inflammation, immunity, and vaccines for Helicobacter. Helicobacter 15(Suppl 1):21–28. https://doi.org/10.1111/j.1523-5378.2010.00777.x
Akhiani AA, Pappo J, Kabok Z, Schon K, Gao W, Franzen LE et al (2002) Protection against Helicobacter pylori infection following immunization is IL-12-dependent and mediated by Th1 Cells. J Immunol 169:6977–6984. https://doi.org/10.4049/jimmunol.169.12.6977
Albanesi C, Fairchild HR, Scarponi C, Pità OD, Donald Y, Leung M et al (2007) IL-4 and IL-13 negatively regulate TNF-alpha- and IFN-gamma -Induced beta-defensin expression through STAT-6, suppressor of cytokine signaling (SOCS)-1, and SOCS-3. J Immunol 179:984–992
Allison CC, Ferrand J, McLeod L, Hassan M, Kaparakis-Liaskos M, Grubman A et al (2013) Nucleotide oligomerization domain 1 enhances IFN-γ signaling in gastric epithelial cells during Helicobacter pylori infection and exacerbates disease severity. J Immunol (Baltimore, Md.: 1950). https://doi.org/10.4049/jimmunol.1200591
Antoni L, Nuding S, Weller D, Gersemann M, Ott G, Wehkamp J et al (2013) Human colonic mucus is a reservoir for antimicrobial peptides. J Crohn’s & colitis. https://doi.org/10.1016/j.crohns.2013.05.006
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(6):955–965. https://doi.org/10.2217/fmb.15.32
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
Bagheri N, Salimzadeh L, Shirzad H (2018) The role of T helper 1-cell response in Helicobacter pylori-infection. Microb Pathog 123:1–8. https://doi.org/10.1016/J.MICPATH.2018.06.033
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
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
Bauer B, Pang E, Holland C, Kessler M, Bartfeld S, Meyer TF (2012a) The Helicobacter pylori virulence effector CagA abrogates human b-defensin 3 expression via inactivation of EGFR signaling. Cell Host Microbe 11:576–586. https://doi.org/10.1016/j.chom.2012.04.013
Bauer B, Wex T, Kuester D, Meyer T, Malfertheiner P (2012b) Differential expression of human beta defensin 2 and 3 in gastric mucosa of Helicobacter pylori-infected individuals. Helicobacter 18:6–12. https://doi.org/10.1111/hel.12000
Beigier-Bompadre M, Moos V, Belogolova E, Allers K, Schneider T, Churin Y et al (2011) Modulation of the CD4 + T-cell response by Helicobacter pylori depends on known virulence factors and bacterial cholesterol and cholesterol alpha-glucoside content. J Infect Dis 204:1339–1348. https://doi.org/10.1093/infdis/jir547
Belogolova E, Bauer B, Pompaiah M, Asakura H, Brinkman V, Ertl C et al (2013) Helicobacter pylori outer membrane protein HopQ identified as a novel T4SS-associated virulence factor. Cell Microbiol, 15, n/a-n/a. https://doi.org/10.1111/cmi.12158
Bik EM, Eckburg PB, Gill SR, Nelson KE, Purdom EA, Francois F et al (2006) Molecular analysis of the bacterial microbiota in the human stomach. Proc Natl Acad Sci USA 103:732–737. https://doi.org/10.1073/pnas.0506655103
Blouin CM, Hamon Y, Gonnord P, Boularan C, Kagan J, Viaris de Lesegno C et al (2016) Glycosylation-dependent IFN-γR partitioning in lipid and actin nanodomains is critical for JAK activation. Cell 166:920–934. https://doi.org/10.1016/j.cell.2016.07.003
Blouin CM, Lamaze C (2013) Interferon gamma receptor: the beginning of the journey. Front Immunol 4:267. https://doi.org/10.3389/fimmu.2013.00267
Boccellato F, Woelffling, S, Imai-Matsushima A, Sanchez G, Goosmann C, Schmid M et al (2018) Polarised epithelial monolayers of the gastric mucosa reveal insights into mucosal homeostasis and defence against infection. Gut gutjnl-2017–314540. https://doi.org/10.1136/gutjnl-2017-314540
Boughan PK, Argent RH, Body-malapel M, Park J-H, Ewings KE, Bowie AG et al (2006) Nucleotide-binding oligomerization domain-1 and epidermal growth factor receptor. J Biol Chem 281:11637–11648. https://doi.org/10.1074/jbc.M510275200
Correia M, Casal S, Vinagre J, Seruca R, Figueiredo C, Touati E et al (2014) Helicobacter pylori’s cholesterol uptake impacts resistance to docosahexaenoic acid. Int J Med Microbiol 304:314–320. https://doi.org/10.1016/J.IJMM.2013.11.018
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. https://doi.org/10.1371/journal.ppat.1002454
Dixon BREA, Radin JN, Piazuelo MB, Contreras DC, Algood HMS, Noto J et al (2016) IL-17a and IL-22 induce expression of antimicrobials in gastrointestinal epithelial cells and may contribute to epithelial cell defense against Helicobacter pylori. PLoS ONE 11:e0148514. https://doi.org/10.1371/journal.pone.0148514
Du S-Y, Wang H-J, Cheng H-H, Chen S-D, Wang LH-C, Wang W-C (2014) Cholesterol glucosylation by Helicobacter pylori delays internalization and arrests phagosome maturation in macrophages. J Microbiol Immunol Infect = Wei mian yu gan ran za zhi https://doi.org/10.1016/j.jmii.2014.05.011
Ermak TH, Giannasca PJ, Nichols R, Myers GA, Nedrud J, Weltzin R et al (1998) 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. https://doi.org/10.1084/JEM.188.12.2277
Fahlgren A, Hammarstrom S, Danielsson A, Hammarstrom M-L (2004) Beta-Defensin-3 and -4 in intestinal epithelial cells display increased mRNA expression in ulcerative colitis. Clin Exp Immunol 137:379–385. https://doi.org/10.1111/j.1365-2249.2004.02543.x
Fehlings M, Drobbe L, Moos V, Renner Viveros P, Hagen J, Beigier-Bompadre M et al (2012) Comparative analysis of the interaction of Helicobacter pylori with human dendritic cells, macrophages, and monocytes. Infect Immun 80:2724–2734. https://doi.org/10.1128/IAI.00381-12
Flanagan K, Modrusan Z, Cornelius J, Chavali A, Kasman I, Komuves L et al (2008) Intestinal epithelial cell up-regulation of LY6 molecules during colitis results in enhanced chemokine secretion. J Immunol (Baltimore, Md.: 1950), 180: 3874–3881. https://doi.org/10.4049/jimmunol.180.6.3874
Gebert B, Fischer W, Weiss E, Hoffmann R, Haas R (2003) Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science (New York, N.Y.), 301: 1099–1102. https://doi.org/10.1126/science.1086871
Gong DH, Turner B, Bhaskar KR, Lamont JT (1990) Lipid binding to gastric mucin: protective effect against oxygen radicals. Am J physiol 259:G681–G686
Hirai Y, Haque M, Yoshida T, Yokota K, Yasuda T, Oguma K (1995) Unique cholesteryl glucosides in Helicobacter pylori: composition and structural analysis. J Bacteriol 177:5327–5333
Hitzler I, Oertli M, Becher B, Agger EM, Müller A (2011) Dendritic cells prevent rather than promote immunity conferred by a Helicobacter vaccine using a mycobacterial adjuvant. Gastroenterology 141:186–196.e1. https://doi.org/10.1053/J.GASTRO.2011.04.009
Ho NK, Ossa JC, Silphaduang U, Johnson R, Johnson-Henry KC, Sherman PM (2012) Enterohemorrhagic escherichia coli O157:H7 shiga toxins inhibit gamma interferon-mediated cellular activation. Infect Immun 80:2307–2315. https://doi.org/10.1128/IAI.00255-12
Horvath DJ, Washington MK, Cope VA, Algood HMS (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
Howitt MR, Lee JY, Lertsethtakarn P, Vogelmann R, Joubert L-M, Ottemann KM et al (2011) ChePep controls Helicobacter pylori infection of the gastric glands and chemotaxis in the epsilonproteobacteria. MBio 2:e00098–11. https://doi.org/10.1128/mbio.00098-11
Hutton ML, D’Costa K, Rossiter AE, Wang L, Turner L, Steer DL et al (2017) A Helicobacter pylori homolog of eukaryotic flotillin is involved in cholesterol accumulation, epithelial cell responses and host colonization. Front cell Infec Microbiol 7:219. https://doi.org/10.3389/fcimb.2017.00219
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 78:4523–4531. https://doi.org/10.1128/IAI.00439-10
Ito Y, Vela JL, Matsumura F, Hoshino H, Tyznik A, Lee H et al (2013) Helicobacter pylori cholesteryl α-glucosides contribute to its pathogenicity and immune response by natural killer T cells. PLoS ONE 8:e78191. https://doi.org/10.1371/journal.pone.0078191
Itoh T, Wakatsuki Y, Yoshida M, Usui T, Matsunaga Y, Kaneko S et al (1999) The vast majority of gastric T cells are polarized to produce T helper 1 type cytokines upon antigenic stimulation despite the absence of Helicobacter pylori infection. J Gastroenterol 34:560–570
Javaheri A, Kruse T, Moonens K, Mejías-Luque R, Debraekeleer A, Asche CI, Tegtmeyer N, Kalali B, Bach NC, Sieber SA, Hill DJ, Königer V, Hauck CR, Moskalenko R, Haas R, Busch DH, Klaile E, Slevogt H, Schmidt A, Backert S, Remaut H, Singer BB, Gerhard M (2016) Helicobacter pylori adhesin HopQ engages in a virulence-enhancing interaction with human CEACAMs. Nat Microbiol 2:16189. https://doi.org/10.1038/nmicrobiol.2016.189
Jimenez-Soto LF, Kutter S, Sewald X, Ertl C, Weiss E, Kapp U et al (2009) Helicobacter pylori type IV secretion apparatus exploits beta1 integrin in a novel RGD-independent manner. PLoS Pathog 5(12):e1000684. https://doi.org/10.1371/journal.ppat.1000684
Johnson KS, Ottemann KM (2018) Colonization, localization, and inflammation: the roles of H. pylori chemotaxis in vivo. Curr Opin Microbiol 41:51–57. https://doi.org/10.1016/j.mib.2017.11.019
Joly S, Organ CC, Johnson GK, McCray PB, Guthmiller JM (2005) Correlation between beta-defensin expression and induction profiles in gingival keratinocytes. Mol Immunol 42:1073–1084. https://doi.org/10.1016/j.molimm.2004.11.001
Kawauchi K, Yagihashi A, Tsuji N, Uehara N, Furuya D, Kobayashi D et al (2006) Human beta-defensin-3 induction in H. pylori-infected gastric mucosal tissues. World J Gastroenterol: WJG 12:5793–5797
Keilberg D, Zavros Y, Shepherd B, Salama NR, Ottemann KM (2016) Spatial and temporal shifts in bacterial biogeography and gland occupation during the development of a chronic infection. MBio 7:e01705–16. https://doi.org/10.1128/mbio.01705-16
Koch M, Mollenkopf H-J, Meyer TF (2016) Macrophages recognize the Helicobacter pylori type IV secretion system in the absence of toll-like receptor signalling. Cell Microbiol 18:137–147. https://doi.org/10.1111/cmi.12492
Königer V, Holsten L, Harrison U, Busch B, Loell E, Zhao Q et al (2016) Helicobacter pylori exploits human CEACAMs via HopQ for adherence and translocation of CagA. Nat Microbiol 2:16188. https://doi.org/10.1038/nmicrobiol.2016.188
Kraft M, Riedel S, Maaser C, Kucharzik T, Steinbuechel A, Domschke W et al (2001) IFN-gamma synergizes with TNF-alpha but not with viable H. pylori in up-regulating CXC chemokine secretion in gastric epithelial cells. Clin Exp Immunol 126:474–481
Kucukazman M, Yavuz B, Sacikara M, Asilturk Z, Ata N, Ertugrul DT et al (2009) The relationship between updated sydney system score and LDL cholesterol levels in patients infected with Helicobacter pylori. Dig Dis Sci 54:604–607. https://doi.org/10.1007/s10620-008-0391-y
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
Lai C-H, Chang Y-C, Du S-Y, Wang H-J, Kuo C-H, Fang S-H et al (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
Lai C-H, Hsu Y-M, Wang H-J, Wang W-C (2013) Manipulation of host cholesterol by Helicobacter pylori for their beneficial ecological niche. BioMedicine 3:27–33. https://doi.org/10.1016/j.biomed.2012.12.002
Lebrun A-H, Wunder C, Hildebrand J, Churin Y, Zähringer U, Lindner B et al (2006) Cloning of a cholesterol-alpha-glucosyltransferase from Helicobacter pylori. J Biol Chem 281:27765–27772. https://doi.org/10.1074/jbc.M603345200
Linz B, Balloux F, Moodley Y, Manica A, Liu H, Roumagnac P et al (2007) An African origin for the intimate association between humans and Helicobacter pylori. Nature 445:915–918. https://doi.org/10.1038/nature05562
Mackenzie JM, Khromykh AA, Parton RG (2007) Cholesterol manipulation by West Nile virus perturbs the cellular immune response. Cell Host Microbe 2:229–239. https://doi.org/10.1016/j.chom.2007.09.003
Malfertheiner P, Selgrad M, Wex T, Romi B, Borgogni E, Spensieri F, et al (2018) Efficacy, immunogenicity, and safety of a parenteral vaccine against Helicobacter pylori in healthy volunteers challenged with a Cag-positive strain: a randomised, placebo-controlled phase 1/2 study. Lancet Gastroenterol Hepatol. https://doi.org/10.1016/s2468-1253(18)30125-0
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
Mejias-Luque R, Zoller J, Anderl F, Loew-Gil E, Vieth M, Adler T et al (2017) Lymphotoxin beta receptor signalling executes Helicobacter pylori-driven gastric inflammation in a T4SS-dependent manner. Gut 66(8):1369–1381. https://doi.org/10.1136/gutjnl-2015-310783
Meyer-Hoffert U, Hornef MW, Henriques-Normark B, Axelsson L-G, Midtvedt T, Pütsep K et al (2008) Secreted enteric antimicrobial activity localises to the mucus surface layer. Gut 57:764–771. https://doi.org/10.1136/gut.2007.141481
Mitchell DJ, Huynh HQ, Ceponis PJM, Jones NL, Sherman PM, Al MET et al (2004) Helicobacter pylori disrupts STAT1-mediated gamma interferon-induced signal transduction in epithelial cells. Infect Immun 72:537–545. https://doi.org/10.1128/IAI.72.1.537
Moonens K, Hamway Y, Neddermann M, Reschke M, Tegtmeyer N, Kruse T, Kammerer R, Mejías-Luque R, Singer BB, Backert S, Gerhard M, Remaut H (2018) Helicobacter pylori adhesin HopQ disrupts trans dimerization in human CEACAMs. EMBO J 37(13):e98665. https://doi.org/10.15252/embj.201798665
Morey P, Pfannkuch L, Pang E, Boccellato F, Sigal M, Imai-Matsushima A et al (2018) Helicobacter pylori depletes cholesterol in gastric glands to prevent interferon gamma signaling and escape the inflammatory response. Gastroenterology 154:1391–1404.e9. https://doi.org/10.1053/j.gastro.2017.12.008
Muhammad JS, Zaidi SF, Zhou Y, Sakurai H, Sugiyama T (2016) Novel epidermal growth factor receptor pathway mediates release of human β-defensin 3 from Helicobacter pylori -infected gastric epithelial cells. Pathogens Dis 74, ftv128. https://doi.org/10.1093/femspd/ftv128
Müller A, Merrell DS, Grimm J, Falkow S (2004) Profiling of microdissected gastric epithelial cells reveals a cell type-specific response to Helicobacter pylori infection. Gastroenterology 127(5):1446–1462. https://doi.org/10.1053/j.gastro.2004.08.054
Müller A, Oertli M, Arnold IC (2011) H. pylori exploits and manipulates innate and adaptive immune cell signaling pathways to establish persistent infection. Cell Commun Signal 9(1):25. https://doi.org/10.1186/1478-811x-9-25
Neumann L, Mueller M, Moos V, Heller F, Meyer TF, Loddenkemper C et al (2016) Mucosal inducible NO synthase-producing IgA + plasma cells in Helicobacter pylori-infected patients. J Immunol 197(5):1801–1808. https://doi.org/10.4049/jimmunol.1501330
Nseir W, Khateeb J, Tatour I, Haiek S, Samara M, Assy N (2010) Long-term statin therapy affects the severity of chronic gastritis. Helicobacter 15:510–515. https://doi.org/10.1111/j.1523-5378.2010.00803.x
Nuding S, Gersemann M, Hosaka Y, Konietzny S, Schaefer C, Beisner J et al (2013) Gastric antimicrobial peptides fail to eradicate Helicobacter pylori infection due to selective induction and resistance. PLoS ONE 8:e73867. https://doi.org/10.1371/journal.pone.0073867
Oertli M, Noben M, Engler DB, Semper RP, Reuter S, Maxeiner J et al (2013) Helicobacter pylori γ-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance. Proc Natl Acad Sci USA 110:3047–3052. https://doi.org/10.1073/pnas.1211248110
Ossa JC, Ho NK, Wine E, Leung N, Gray-Owen SD, Sherman PM (2013) Adherent-invasive Escherichia coli blocks interferon-γ-induced signal transducer and activator of transcription (STAT)-1 in human intestinal epithelial cells. Cell Microbiol 15:446–457. https://doi.org/10.1111/cmi.12048
Ostaff MJ, Stange EF, Wehkamp J (2013) Antimicrobial peptides and gut microbiota in homeostasis and pathology. EMBO Mol Med 5:1465–1483. https://doi.org/10.1002/emmm.201201773
Pachathundikandi SK, Müller A, Backert S (2016) Inflammasome activation by Helicobacter pylori and its implications for persistence and immunity. Curr Top Microbiol Immunol 397:117–131. https://doi.org/10.1007/978-3-319-41171-2_6
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(6):454–474. https://doi.org/10.4161/gmic.27001
Pfannkuch L, Hurwitz R, Traulsen J, Kosma P, Schmid M, Meyer T (2018) ADP heptose, a novel pathogen associated molecular pattern associated with Helicobacter pylori type 4 secretion. BioRxiv. https://doi.org/10.1101/405951
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
Ricci V, Galmiche A, Doye A, Necchi V, Solcia E, Boquet P (2000) High cell sensitivity to Helicobacter pylori VacA toxin depends on a GPI-anchored protein and is not blocked by inhibition of the clathrin-mediated pathway of endocytosis. Mol Biol Cell 11:3897–3909. https://doi.org/10.1091/mbc.11.11.3897
Salama NR, Hartung ML, Müller A (2013) Life in the human stomach: persistence strategies of the bacterial pathogen Helicobacter pylori. Nat Rev Microbiol, advance on. https://doi.org/10.1038/nrmicro3016
Sawai N, Kita M, Kodama T, Tanahashi T, Yamaoka Y, Tagawa Y et al (1999) Role of gamma interferon in Helicobacter pylori-induced gastric inflammatory responses in a mouse model. Infect Immun 67:279–285
Sayi A, Kohler E, Hitzler I, Arnold I, Schwendener R, Rehrauer H et al (2009) The CD4 + T cell-mediated IFN-gamma response to Helicobacter infection is essential for clearance and determines gastric cancer risk. J Immunol (Baltimore, Md.: 1950), 182:7085–101. https://doi.org/10.4049/jimmunol.0803293
Schreiber S, Bücker R, Groll C, Azevedo-Vethacke M, Garten D, Scheid P et al (2005) Rapid loss of motility of Helicobacter pylori in the gastric lumen in vivo. Infect Immun 73:1584–1589. https://doi.org/10.1128/IAI.73.3.1584-1589.2005
Sehgal PB, Guo GG, Shah M, Kumar V, Patel K (2002) Cytokine signaling: STATS in plasma membrane rafts. J Biol Chem 277:12067–12074. https://doi.org/10.1074/jbc.M200018200
Sen S, Roy K, Mukherjee S, Mukhopadhyay R, Roy S (2011) Restoration of IFNγR subunit assembly, IFNγ signaling and parasite clearance in Leishmania donovani infected macrophages: role of membrane cholesterol. PLoS Pathog 7:e1002229. https://doi.org/10.1371/journal.ppat.1002229
Shimomura H, Hosoda K, Hayashi S, Yokota K, Hirai Y (2012) Phosphatidylethanolamine of Helicobacter pylori functions as a steroid-binding lipid in the assimilation of free cholesterol and 3β-hydroxl steroids into the bacterial cell membrane. J Bacteriol 194:2658–2667. https://doi.org/10.1128/JB.00105-12
Shimomura H, Hosoda K, McGee DJ, Hayashi S, Yokota K, Hirai Y (2013) Detoxification of 7-dehydrocholesterol fatal to Helicobacter pylori is a novel role of cholesterol glucosylation. J Bacteriol 195:359–367. https://doi.org/10.1128/JB.01495-12
Simons K, Sampaio JL (2011) Membrane organization and lipid rafts. Cold Spring Harb Perspect Biol 3:a004697. https://doi.org/10.1101/cshperspect.a004697
Singh PP, Singh S (2013) Statins are associated with reduced risk of gastric cancer: a systematic review and meta-analysis. Ann Oncol 24(7):1721–1730. https://doi.org/10.1093/annonc/mdt150
Smythies LE, Waites KB, Lindsey JR, Harris PR, Ghiara P, Smith PD (2000) Helicobacter pylori-induced mucosal inflammation is Th1 mediated and exacerbated in IL-4, but not IFN-gamma, gene-deficient mice. J Immunol (Baltimore, Md.: 1950), 165:1022–1029
Stein SC, Faber E, Bats SH, Murillo T, Speidel Y, Coombs N et al (2017) Helicobacter pylori modulates host cell responses by CagT4SS-dependent translocation of an intermediate metabolite of LPS inner core heptose biosynthesis. PLoS Pathog 13:e1006514. https://doi.org/10.1371/journal.ppat.1006514
Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL et al (2018) Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 18:318–327. https://doi.org/10.1016/S1473-3099(17)30753-3
Takaoka A, Mitani Y, Suemori H, Sato M, Yokochi T, Noguchi S et al (2000) Cross talk between interferon-gamma and -alpha/beta signaling components in caveolar membrane domains. Science 288:2357–2360. https://doi.org/10.1126/science.288.5475.2357
Tegtmeyer N, Neddermann M, Asche CI, Backert S (2017a) Subversion of host kinases: a key network in cellular signaling hijacked by Helicobacter pylori CagA. Mol Microbiol 105(3):358–372. https://doi.org/10.1111/mmi.13707
Tegtmeyer N, Wessler S, Necchi V, Rohde M, Harrer A, Rau TT, Asche CI, Boehm M, Loessner H, Figueiredo C, Naumann M, Palmisano R, Solcia E, Ricci V, Backert S (2017b) Helicobacter pylori employs a unique basolateral type IV secretion mechanism for CagA delivery. Cell Host Microbe 22(4):552–560.e5. https://doi.org/10.1016/j.chom.2017.09.005
Tegtmeyer N, Harrer A, Schmitt V, Singer BB, Backert S (2019) Expression of CEACAM1 or CEACAM5 in AZ-521 cells restores the type IV secretion deficiency for translocation of CagA by Helicobacter pylori. Cell Microbiol 21:e12965. https://doi.org/10.1111/cmi.12965
Tran LS, Chonwerawong M, Ferrero RL (2017) Regulation and functions of inflammasome-mediated cytokines in Helicobacter pylori infection. Microbes Infect 19(9–10):449–458. https://doi.org/10.1016/j.micinf.2017.06.005
Vaishnava S, Yamamoto M, Severson KM, Ruhn KA, Yu X, Koren O et al (2011) The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science (New York, N.Y.), 334: 255–8. https://doi.org/10.1126/science.1209791
Velin D, Favre L, Bernasconi E, Bachmann D, Pythoud C, Saiji E et al (2009) Interleukin-17 is a critical mediator of vaccine-induced reduction of Helicobacter infection in the mouse model. Gastroenterology 136:2237–2246.e1. https://doi.org/10.1053/J.GASTRO.2009.02.077
Velin D, Straubinger K, Gerhard M (2016) Inflammation, immunity, and vaccines for Helicobacter pylori infection. Helicobacter 21(Suppl 1):26–29. https://doi.org/10.1111/hel.12336
Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP et al (2004) Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol 5:1166–1174. https://doi.org/10.1038/ni1131
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
Wang Y-C, Chen C-L, Sheu B-S, Yang Y-J, Tseng P-C, Hsieh C-Y et al (2014) Helicobacter pylori infection activates src homology-2 domain-containing phosphatase 2 to suppress IFN-γ signaling. J Immunol (Baltimore, Md.: 1950) 193:4149–58. https://doi.org/10.4049/jimmunol.1400594
Watanabe T, Asano N, Fichtner-Feigl S, Gorelick PL, Tsuji Y, Matsumoto Y et al (2010) NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway. J Clin Investig 120:1645–1662. https://doi.org/10.1172/JCI39481
Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R (2004) IL-22 increases the innate immunity of tissues. Immunity 21:241–254
Wunder C, Churin Y, Winau F, Warnecke D, Vieth M, Lindner B et al (2006) Cholesterol glucosylation promotes immune evasion by Helicobacter pylori. Nat Med 12:1030–1038. https://doi.org/10.1038/nm1480
Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q et al (2008) Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 14(3):282–289. https://doi.org/10.1038/nm1720
Zhuang Y, Cheng P, Liu XF, Peng LS, Li BS, Wang TT et al (2015) A pro-inflammatory role for Th22 cells in Helicobacter pylori-associated gastritis. Gut 64(9):1368–1378. https://doi.org/10.1136/gutjnl-2014-307020
Zimmermann S, Pfannkuch L, Al-Zeer MA, Bartfeld S, Koch M, Liu J et al (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
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Morey, P., Meyer, T.F. (2019). The Sweeping Role of Cholesterol Depletion in the Persistence of Helicobacter pylori Infections. In: Backert, S. (eds) Molecular Mechanisms of Inflammation: Induction, Resolution and Escape by Helicobacter pylori. Current Topics in Microbiology and Immunology, vol 421. Springer, Cham. https://doi.org/10.1007/978-3-030-15138-6_9
Download citation
DOI: https://doi.org/10.1007/978-3-030-15138-6_9
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-15137-9
Online ISBN: 978-3-030-15138-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)