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NOD1 and NOD2 and the Immune Response to Bacteria

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Molecular Genetics of Inflammatory Bowel Disease

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Abstract

The mammalian host has evolved to develop a diverse array of innate immune receptors and strategies to defend itself against infection by microbial pathogens. These germ-line encoded and conserved microbial receptors, called pattern recognition receptors (PRRs), are associated with the membranes or within the cytosol of host cells. PRRs enable the host to rapidly respond to pathogen-associated molecular patterns (PAMPs), as a first line of defense against microbial intrusion. Signaling via PRRs enables the host to mount a rapid and non-specific immune response that results in inflammation and ultimately the activation of the adaptive immune system.

The host has a variety of PRRs, including the membrane-bound Toll-like receptors (TLRs) and the cytoplasmic nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) protein family. In this chapter, we will focus predominantly on NOD1 and NOD2, which are members of the NLR family of proteins, and the role they have in the initiation and development of an immune response to bacteria. We will discuss the various methods whereby bacteria are detected and can induce signaling via NOD receptors and the role of NOD proteins in human disease, especially the role of NOD2 in Crohn’s disease.

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References

  1. Strober W, Murray PJ, Kitani A, Watanabe T (2006) Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol 6(1):9–20

    Article  CAS  PubMed  Google Scholar 

  2. Mukherjee T, Hovingh ES, Foerster EG, Abdel-Nour M, Philpott DJ, Girardin SE (2019) NOD1 and NOD2 in inflammation, immunity and disease. Arch Biochem Biophys 670:69–81

    Article  CAS  PubMed  Google Scholar 

  3. Clarke TB, Weiser JN (2011) Intracellular sensors of extracellular bacteria. Immunol Rev 243(1):9–5

    Article  CAS  PubMed  Google Scholar 

  4. Ausubel FM (2005) Are innate immune signaling pathways in plants and animals conserved? Nat Immunol 6(10):973–979

    Article  CAS  PubMed  Google Scholar 

  5. Philpott DJ, Girardin SE (2010) Nod-like receptors: sentinels at host membranes. Curr Opin Immunol 22(4):428–434

    Article  CAS  PubMed  Google Scholar 

  6. Werts C, Rubino S, Ling A, Girardin SE, Philpott DJ (2011) Nod-like receptors in intestinal homeostasis, inflammation, and cancer. J Leukoc Biol 90(3):471–482

    Article  CAS  PubMed  Google Scholar 

  7. Ting JP, Lovering RC, Alnemri ES, Bertin J, Boss JM, Davis BK et al (2008) The NLR gene family: a standard nomenclature. Immunity 28(3):285–287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Inohara N, Nunez G (2003) NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 3(5):371–382

    Article  CAS  PubMed  Google Scholar 

  9. Maekawa S, Ohto U, Shibata T, Miyake K, Shimizu T (2016) Crystal structure of NOD2 and its implications in human disease. Nat Commun 7:11813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tanabe T, Chamaillard M, Ogura Y, Zhu L, Qiu S, Masumoto J et al (2004) Regulatory regions and critical residues of NOD2 involved in muramyl dipeptide recognition. EMBO J 23(7):1587–1597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Girardin SE, Jéhanno M, Mengin-Lecreulx D, Sansonetti PJ, Alzari PM, Philpott DJ (2005) Identification of the critical residues involved in peptidoglycan detection by Nod1. J Biol Chem 280(46):38648–38656

    Article  CAS  PubMed  Google Scholar 

  12. Inohara N, Ogura Y, Chen FF, Muto A, Nunez G (2001) Human Nod1 confers responsiveness to bacterial lipopolysaccharides. J Biol Chem 276(4):2551–2554

    Article  CAS  PubMed  Google Scholar 

  13. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R et al (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411(6837):603–606

    Article  CAS  PubMed  Google Scholar 

  14. Girardin SE, Tournebize R, Mavris M, Page AL, Li X, Stark GR et al (2001) CARD4/Nod1 mediates NF-kappaB and JNK activation by invasive Shigella flexneri. EMBO Rep 2(8):736–742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Inohara N, Koseki T, del Peso L, Hu Y, Yee C, Chen S et al (1999) Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB. J Biol Chem 274(21):14560–14567

    Article  CAS  PubMed  Google Scholar 

  16. Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G et al (2003) Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 278(11):8869–8872

    Article  CAS  PubMed  Google Scholar 

  17. Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J et al (2003) Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn’s disease. J Biol Chem 278(8):5509–5512

    Article  CAS  PubMed  Google Scholar 

  18. Fritz JH, Girardin SE, Fitting C, Werts C, Mengin-Lecreulx D, Caroff M et al (2005) Synergistic stimulation of human monocytes and dendritic cells by Toll-like receptor 4 and NOD1- and NOD2-activating agonists. Eur J Immunol 35(8):2459–2470

    Article  CAS  PubMed  Google Scholar 

  19. Enoksson M, Ejendal KF, McAlpine S, Nilsson G, Lunderius-Andersson C (2011) Human cord blood-derived mast cells are activated by the Nod1 agonist M-TriDAP to release pro-inflammatory cytokines and chemokines. J Innate Immun 3(2):142–149

    Article  CAS  PubMed  Google Scholar 

  20. Qiu F, Maniar A, Diaz MQ, Chapoval AI, Medvedev AE (2011) Activation of cytokine-producing and antitumor activities of natural killer cells and macrophages by engagement of Toll-like and NOD-like receptors. Innate Immun 17(4):375–387

    Article  CAS  PubMed  Google Scholar 

  21. Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L et al (2003) An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol 4(7):702–707

    Article  CAS  PubMed  Google Scholar 

  22. Girardin SE, Boneca IG, Carneiro LA, Antignac A, Jehanno M, Viala J et al (2003) Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science 300(5625):1584–1587

    Article  CAS  PubMed  Google Scholar 

  23. Chamaillard M, Girardin SE, Viala J, Philpott DJ (2003) Nods, Nalps and Naip: intracellular regulators of bacterial-induced inflammation. Cell Microbiol 5(9):581–592

    Article  CAS  PubMed  Google Scholar 

  24. Magalhaes JG, Philpott DJ, Nahori MA, Jehanno M, Fritz J, Bourhis LL et al (2005) Murine Nod1 but not its human orthologue mediates innate immune detection of tracheal cytotoxin. EMBO Rep 6(12):1201–1207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G (2001) Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 276(7):4812–4818

    Article  CAS  PubMed  Google Scholar 

  26. Rahman MK, Midtling EH, Svingen PA, Xiong Y, Bell MP, Tung J et al (2010) The pathogen recognition receptor NOD2 regulates human FOXP3+ T cell survival. J Immunol 184(12):7247–7256

    Article  CAS  PubMed  Google Scholar 

  27. Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu Y, Weiser JN (2010) Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat Med 16(2):228–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hisamatsu T, Suzuki M, Reinecker HC, Nadeau WJ, McCormick BA, Podolsky DK (2003) CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells. Gastroenterology 124(4):993–1000

    Article  CAS  PubMed  Google Scholar 

  29. Gutierrez O, Pipaon C, Inohara N, Fontalba A, Ogura Y, Prosper F et al (2002) Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-kappa B activation. J Biol Chem 277(44):41701–41705

    Article  CAS  PubMed  Google Scholar 

  30. Rosenstiel P, Fantini M, Brautigam K, Kuhbacher T, Waetzig GH, Seegert D et al (2003) TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells. Gastroenterology 124(4):1001–1009

    Article  CAS  PubMed  Google Scholar 

  31. Shaw PJ, Barr MJ, Lukens JR, McGargill MA, Chi H, Mak TW et al (2011) Signaling via the RIP2 adaptor protein in central nervous system-infiltrating dendritic cells promotes inflammation and autoimmunity. Immunity 34(1):75–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhao L, Hu P, Zhou Y, Purohit J, Hwang D (2011) NOD1 activation induces proinflammatory gene expression and insulin resistance in 3T3-L1 adipocytes. Am J Physiol Endocrinol Metab 301(4):E587–E598

    Article  CAS  PubMed  Google Scholar 

  33. Silva GK, Gutierrez FR, Guedes PM, Horta CV, Cunha LD, Mineo TW et al (2010) Cutting edge: nucleotide-binding oligomerization domain 1-dependent responses account for murine resistance against Trypanosoma cruzi infection. J Immunol 184(3):1148–1152

    Article  CAS  PubMed  Google Scholar 

  34. Finney CA, Lu Z, LeBourhis L, Philpott DJ, Kain KC (2009) Disruption of Nod-like receptors alters inflammatory response to infection but does not confer protection in experimental cerebral malaria. Am J Trop Med Hyg 80(5):718–722

    Article  CAS  PubMed  Google Scholar 

  35. Sorbara MT, Philpott DJ (2011) Peptidoglycan: a critical activator of the mammalian immune system during infection and homeostasis. Immunol Rev 243(1):40–60

    Article  CAS  PubMed  Google Scholar 

  36. Fritz JH, Ferrero RL, Philpott DJ, Girardin SE (2006) Nod-like proteins in immunity, inflammation and disease. Nat Immunol 7(12):1250–1257

    Article  CAS  PubMed  Google Scholar 

  37. Hasegawa M, Fujimoto Y, Lucas PC, Nakano H, Fukase K, Nunez G et al (2008) A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation. EMBO J 27(2):373–383

    Article  CAS  PubMed  Google Scholar 

  38. Inohara N, Koseki T, Lin J, del Peso L, Lucas PC, Chen FF et al (2000) An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways. J Biol Chem 275(36):27823–27831

    CAS  PubMed  Google Scholar 

  39. Meylan E, Tschopp J (2005) The RIP kinases: crucial integrators of cellular stress. Trends Biochem Sci 30(3):151–159

    Article  CAS  PubMed  Google Scholar 

  40. Kobayashi K, Inohara N, Hernandez LD, Galan JE, Nunez G, Janeway CA et al (2002) RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 416(6877):194–199

    Article  CAS  PubMed  Google Scholar 

  41. Bertrand MJ, Doiron K, Labbe K, Korneluk RG, Barker PA, Saleh M (2009) Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2. Immunity 30(6):789–801

    Article  CAS  PubMed  Google Scholar 

  42. Krieg A, Correa RG, Garrison JB, Le Negrate G, Welsh K, Huang Z et al (2009) XIAP mediates NOD signaling via interaction with RIP2. Proc Natl Acad Sci U S A 106(34):14524–14529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Damgaard RB, Nachbur U, Yabal M, Wong WW, Fiil BK, Kastirr M et al (2012) The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Mol Cell 46(6):746–758

    Article  CAS  PubMed  Google Scholar 

  44. Yang Y, Yin C, Pandey A, Abbott D, Sassetti C, Kelliher MA (2007) NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2. J Biol Chem 282(50):36223–36229

    Article  CAS  PubMed  Google Scholar 

  45. Abbott DW, Wilkins A, Asara JM, Cantley LC (2004) The Crohn’s disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO. Curr Biol 14(24):2217–2227

    Article  CAS  PubMed  Google Scholar 

  46. 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(11):1166–1174

    Article  CAS  PubMed  Google Scholar 

  47. Gong Q, Long Z, Zhong FL, Teo DET, Jin Y, Yin Z et al (2018) Structural basis of RIP2 activation and signaling. Nat Commun 9(1):4993

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Pellegrini E, Desfosses A, Wallmann A, Schulze WM, Rehbein K, Mas P et al (2018) RIP2 filament formation is required for NOD2 dependent NF-κB signalling. Nat Commun 9(1):4043

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Wu B, Hur S (2015) How RIG-I like receptors activate MAVS. Curr Opin Virol 12:91–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kufer TA, Kremmer E, Banks DJ, Philpott DJ (2006) Role for erbin in bacterial activation of Nod2. Infect Immun 74(6):3115–3124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. McDonald C, Chen FF, Ollendorff V, Ogura Y, Marchetto S, Lecine P et al (2005) A role for Erbin in the regulation of Nod2-dependent NF-kappaB signaling. J Biol Chem 280(48):40301–40309

    Article  CAS  PubMed  Google Scholar 

  52. Richmond AL, Kabi A, Homer CR, Marina-Garcia N, Nickerson KP, Nesvizhskii AI et al (2012) The nucleotide synthesis enzyme CAD inhibits NOD2 antibacterial function in human intestinal epithelial cells. Gastroenterology 142(7):1483–92 e6

    Article  CAS  PubMed  Google Scholar 

  53. Warner N, Burberry A, Pliakas M, McDonald C, Núñez G (2014) A genome-wide small interfering RNA (siRNA) screen reveals nuclear factor-κB (NF-κB)-independent regulators of NOD2-induced interleukin-8 (IL-8) secretion. J Biol Chem 289(41):28213–28224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Magalhaes JG, Sorbara MT, Girardin SE, Philpott DJ (2010) What is new with Nods? Curr Opin Immunol 23(1):29–34

    Article  PubMed  CAS  Google Scholar 

  55. Tattoli I, Travassos LH, Carneiro LA, Magalhaes JG, Girardin SE (2007) The Nodosome: Nod1 and Nod2 control bacterial infections and inflammation. Semin Immunopathol 29(3):289–301

    Article  CAS  PubMed  Google Scholar 

  56. Petnicki-Ocwieja T, Hrncir T, Liu YJ, Biswas A, Hudcovic T, Tlaskalova-Hogenova H et al (2009) Nod2 is required for the regulation of commensal microbiota in the intestine. Proc Natl Acad Sci U S A 106(37):15813–15818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Robertson SJ, Zhou JY, Geddes K, Rubino SJ, Cho JH, Girardin SE et al (2013) Nod1 and Nod2 signaling does not alter the composition of intestinal bacterial communities at homeostasis. Gut Microbes 4(3):222–231

    Article  PubMed  PubMed Central  Google Scholar 

  58. Shanahan MT, Carroll IM, Grossniklaus E, White A, von Furstenberg RJ, Barner R et al (2014) Mouse Paneth cell antimicrobial function is independent of Nod2. Gut 63(6):903–910

    Article  CAS  PubMed  Google Scholar 

  59. Wehkamp J, Harder J, Weichenthal M, Schwab M, Schaffeler E, Schlee M et al (2004) NOD2 (CARD15) mutations in Crohn’s disease are associated with diminished mucosal alpha-defensin expression. Gut 53(11):1658–1664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Vaishnava S, Behrendt CL, Ismail AS, Eckmann L, Hooper LV (2008) Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci U S A 105(52):20858–20863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Bouskra D, Brezillon C, Berard M, Werts C, Varona R, Boneca IG et al (2008) Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456(7221):507–510

    Article  CAS  PubMed  Google Scholar 

  62. Ganz T (2003) Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol 3(9):710–720

    Article  CAS  PubMed  Google Scholar 

  63. Boughan PK, Argent RH, Body-Malapel M, Park JH, Ewings KE, Bowie AG et al (2006) Nucleotide-binding oligomerization domain-1 and epidermal growth factor receptor: critical regulators of beta-defensins during Helicobacter pylori infection. J Biol Chem 281(17):11637–11648

    Article  CAS  PubMed  Google Scholar 

  64. Grubman A, Kaparakis M, Viala J, Allison C, Badea L, Karrar A et al (2010) The innate immune molecule, NOD1, regulates direct killing of Helicobacter pylori by antimicrobial peptides. Cell Microbiol 12(5):626–639

    Article  CAS  PubMed  Google Scholar 

  65. Voss E, Wehkamp J, Wehkamp K, Stange EF, Schroder JM, Harder J (2006) NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2. J Biol Chem 281(4):2005–2011

    Article  CAS  PubMed  Google Scholar 

  66. Masumoto J, Yang K, Varambally S, Hasegawa M, Tomlins SA, Qiu S et al (2006) Nod1 acts as an intracellular receptor to stimulate chemokine production and neutrophil recruitment in vivo. J Exp Med 203(1):203–213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kim YG, Kamada N, Shaw MH, Warner N, Chen GY, Franchi L et al (2011) The Nod2 sensor promotes intestinal pathogen eradication via the chemokine CCL2-dependent recruitment of inflammatory monocytes. Immunity 34(5):769–780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lysenko ES, Clarke TB, Shchepetov M, Ratner AJ, Roper DI, Dowson CG et al (2007) Nod1 signaling overcomes resistance of S. pneumoniae to opsonophagocytic killing. PLoS Pathog 3(8):e118

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Totemeyer S, Sheppard M, Lloyd A, Roper D, Dowson C, Underhill D et al (2006) IFN-gamma enhances production of nitric oxide from macrophages via a mechanism that depends on nucleotide oligomerization domain-2. J Immunol 176(8):4804–4810

    Article  PubMed  Google Scholar 

  70. Le Bourhis L, Magalhaes JG, Selvanantham T, Travassos LH, Geddes K, Fritz JH et al (2009) Role of Nod1 in mucosal dendritic cells during salmonella pathogenicity island 1-independent Salmonella enterica serovar Typhimurium infection. Infect Immun 77(10):4480–4486

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Mosa A, Trumstedt C, Eriksson E, Soehnlein O, Heuts F, Janik K et al (2009) Nonhematopoietic cells control the outcome of infection with Listeria monocytogenes in a nucleotide oligomerization domain 1-dependent manner. Infect Immun 77(7):2908–2918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Scott MJ, Chen C, Sun Q, Billiar TR (2010) Hepatocytes express functional NOD1 and NOD2 receptors: a role for NOD1 in hepatocyte CC and CXC chemokine production. J Hepatol 53(4):693–701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Moreno L, McMaster SK, Gatheral T, Bailey LK, Harrington LS, Cartwright N et al (2010) NOD1 is a dominant pathway for NOS2 induction in vascular smooth muscle cells: comparison with TLR4 responses in macrophages. Br J Pharmacol 160:1997–2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Shimada K, Chen S, Dempsey PW, Sorrentino R, Alsabeh R, Slepenkin AV et al (2009) The NOD/RIP2 pathway is essential for host defenses against Chlamydophila pneumoniae lung infection. PLoS Pathog 5(4):e1000379

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Simonsen A, Tooze SA (2009) Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes. J Cell Biol 186(6):773–782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Deretic V, Levine B (2009) Autophagy, immunity, and microbial adaptations. Cell Host Microbe 5(6):527–549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Travassos LH, Carneiro LA, Ramjeet M, Hussey S, Kim YG, Magalhaes JG et al (2009) Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol 11(1):55–62

    Article  PubMed  CAS  Google Scholar 

  78. Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P et al (2010) NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 16(1):90–97

    Article  CAS  PubMed  Google Scholar 

  79. Homer CR, Richmond AL, Rebert NA, Achkar JP, McDonald C (2010) ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn’s disease pathogenesis. Gastroenterology 139(5):1630–41.e2

    Article  CAS  PubMed  Google Scholar 

  80. Sorbara MT, Ellison LK, Ramjeet M, Travassos LH, Jones NL, Girardin SE et al (2013) The protein ATG16L1 suppresses inflammatory cytokines induced by the intracellular sensors Nod1 and Nod2 in an autophagy-independent manner. Immunity 39(5):858–873

    Article  CAS  PubMed  Google Scholar 

  81. Marchiando AM, Ramanan D, Ding Y, Gomez LE, Hubbard-Lucey VM, Maurer K et al (2013) A deficiency in the autophagy gene Atg16L1 enhances resistance to enteric bacterial infection. Cell Host Microbe 14(2):216–224

    Article  CAS  PubMed  Google Scholar 

  82. Chu H, Khosravi A, Kusumawardhani IP, Kwon AH, Vasconcelos AC, Cunha LD et al (2016) Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science 352(6289):1116–1120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Keestra AM, Winter MG, Auburger JJ, Frässle SP, Xavier MN, Winter SE et al (2013) Manipulation of small Rho GTPases is a pathogen-induced process detected by NOD1. Nature 496(7444):233–237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Keestra-Gounder AM, Byndloss MX, Seyffert N, Young BM, Chávez-Arroyo A, Tsai AY et al (2016) NOD1 and NOD2 signalling links ER stress with inflammation. Nature 532(7599):394–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Xu XL, Lee RT, Fang HM, Wang YM, Li R, Zou H et al (2008) Bacterial peptidoglycan triggers Candida albicans hyphal growth by directly activating the adenylyl cyclase Cyr1p. Cell Host Microbe 4(1):28–39

    Article  CAS  PubMed  Google Scholar 

  86. Huang Z, Wang J, Xu X, Wang H, Qiao Y, Chu WC et al (2019) Antibody neutralization of microbiota-derived circulating peptidoglycan dampens inflammation and ameliorates autoimmunity. Nat Microbiol 4(5):766–773

    Article  CAS  PubMed  Google Scholar 

  87. Molinaro R, Mukherjee T, Flick R, Philpott D, Girardin S (2019) Trace levels of peptidoglycan in serum underlie the NOD-dependent cytokine response to endoplasmic reticulum stress. J Biol Chem 294(22):9007–9015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bouskra D, Brézillon C, Bérard M, Werts C, Varona R, Boneca IG et al (2008) Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456(7221):507–510

    Article  CAS  PubMed  Google Scholar 

  89. Rehman A, Sina C, Gavrilova O, Häsler R, Ott S, Baines JF et al (2011) Nod2 is essential for temporal development of intestinal microbial communities. Gut 60(10):1354–1362

    Article  CAS  PubMed  Google Scholar 

  90. Robertson S, Lemire P, Maughan H, Goethel A, Turpin W, Bedrani L et al (2019) Comparison of co-housing and littermate methods for microbiota standardization in mouse models. Cell Rep 27(6):1910–1919.e2

    Article  CAS  PubMed  Google Scholar 

  91. Turpin W, Espin-Garcia O, Xu W, Silverberg MS, Kevans D, Smith MI et al (2016) Association of host genome with intestinal microbial composition in a large healthy cohort. Nat Genet 48(11):1413–1417

    Article  CAS  PubMed  Google Scholar 

  92. Robertson SJ, Goethel A, Girardin SE, Philpott DJ (2018) Innate immune influences on the gut microbiome: lessons from mouse models. Trends Immunol 39(12):992–1004

    Article  CAS  PubMed  Google Scholar 

  93. Robertson SJ, Geddes K, Maisonneuve C, Streutker CJ, Philpott DJ (2016) Resilience of the intestinal microbiota following pathogenic bacterial infection is independent of innate immunity mediated by NOD1 or NOD2. Microbes Infect 18(7–8):460–471

    Article  CAS  PubMed  Google Scholar 

  94. Goethel A, Turpin W, Rouquier S, Zanello G, Robertson SJ, Streutker CJ et al (2019) Nod2 influences microbial resilience and susceptibility to colitis following antibiotic exposure. Mucosal Immunol 12(3):720–732

    Article  CAS  PubMed  Google Scholar 

  95. Shaw SY, Blanchard JF, Bernstein CN (2010) Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease. Am J Gastroenterol 105(12):2687–2692

    Article  PubMed  Google Scholar 

  96. Fritz JH, Le Bourhis L, Sellge G, Magalhaes JG, Fsihi H, Kufer TA et al (2007) Nod1-mediated innate immune recognition of peptidoglycan contributes to the onset of adaptive immunity. Immunity 26(4):445–459

    Article  CAS  PubMed  Google Scholar 

  97. Magalhães JG, Lee J, Geddes K, Rubino S, Philpott DJ, Girardin SE (2011) Essential role of Rip2 in the modulation of innate and adaptive immunity triggered by Nod1 and Nod2 ligands. Eur J Immunol 41(5):1445–1455

    Article  PubMed  CAS  Google Scholar 

  98. Magalhaes JG, Rubino SJ, Travassos LH, Le Bourhis L, Duan W, Sellge G et al (2011) Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation. Proc Natl Acad Sci U S A 108(36):14896–14901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Freytag LC, Clements JD (2005) Mucosal adjuvants. Vaccine 23(15):1804–1813

    Article  CAS  PubMed  Google Scholar 

  100. Kim D, Kim YG, Seo SU, Kim DJ, Kamada N, Prescott D et al (2016) Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin. Nat Med 22(5):524–530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ouyang W, Kolls JK, Zheng Y (2008) The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28(4):454–467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Colonna M (2009) Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity 31(1):15–23

    Article  CAS  PubMed  Google Scholar 

  103. Geddes K, Rubino SJ, Magalhães JG, Streutker C, Le Bourhis L, Cho JH et al (2011) Identification of an innate T helper type 17 response to intestinal bacterial pathogens. Nat Med 17(7):837–844

    Article  CAS  PubMed  Google Scholar 

  104. Wing K, Sakaguchi S (2010) Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol 11(1):7–13

    Article  CAS  PubMed  Google Scholar 

  105. Noguchi E, Homma Y, Kang X, Netea MG, Ma X (2009) A Crohn’s disease-associated NOD2 mutation suppresses transcription of human IL10 by inhibiting activity of the nuclear ribonucleoprotein hnRNP-A1. Nat Immunol 10(5):471–479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Hedl M, Li J, Cho JH, Abraham C (2007) Chronic stimulation of Nod2 mediates tolerance to bacterial products. Proc Natl Acad Sci U S A 104(49):19440–19445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sun R, Hedl M, Abraham C (2019) Twist1 and Twist2 induce human macrophage memory upon chronic innate receptor treatment by HDAC-mediated deacetylation of cytokine promoters. J Immunol 202(11):3297–3308

    Article  CAS  PubMed  Google Scholar 

  108. Opitz B, Forster S, Hocke AC, Maass M, Schmeck B, Hippenstiel S et al (2005) Nod1-mediated endothelial cell activation by Chlamydophila pneumoniae. Circ Res 96(3):319–326

    Article  CAS  PubMed  Google Scholar 

  109. Opitz B, Puschel A, Beermann W, Hocke AC, Forster S, Schmeck B et al (2006) Listeria monocytogenes activated p38 MAPK and induced IL-8 secretion in a nucleotide-binding oligomerization domain 1-dependent manner in endothelial cells. J Immunol 176(1):484–490

    Article  CAS  PubMed  Google Scholar 

  110. Kim JG, Lee SJ, Kagnoff MF (2004) Nod1 is an essential signal transducer in intestinal epithelial cells infected with bacteria that avoid recognition by toll-like receptors. Infect Immun 72(3):1487–1495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Boneca IG, Dussurget O, Cabanes D, Nahori MA, Sousa S, Lecuit M et al (2007) A critical role for peptidoglycan N-deacetylation in Listeria evasion from the host innate immune system. Proc Natl Acad Sci U S A 104(3):997–1002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Pott J, Basler T, Duerr CU, Rohde M, Goethe R, Hornef MW (2009) Internalization-dependent recognition of Mycobacterium aviumssp. paratuberculosisby intestinal epithelial cells. Cell Microbiol 11(12):1802–1815

    Article  CAS  PubMed  Google Scholar 

  113. Slevogt H, Seybold J, Tiwari KN, Hocke AC, Jonatat C, Dietel S et al (2007) Moraxella catarrhalis is internalized in respiratory epithelial cells by a trigger-like mechanism and initiates a TLR2- and partly NOD1-dependent inflammatory immune response. Cell Microbiol 9(3):694–707

    Article  CAS  PubMed  Google Scholar 

  114. Ferwerda G, Girardin SE, Kullberg BJ, Le Bourhis L, de Jong DJ, Langenberg DM et al (2005) NOD2 and toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis. PLoS Pathog 1(3):279–285

    Article  CAS  PubMed  Google Scholar 

  115. Brooks MN, Rajaram MV, Azad AK, Amer AO, Valdivia-Arenas MA, Park JH et al (2011) NOD2 controls the nature of the inflammatory response and subsequent fate of Mycobacterium tuberculosis and M. bovis BCG in human macrophages. Cell Microbiol 13(3):402–418

    Article  CAS  PubMed  Google Scholar 

  116. Opitz B, Puschel A, Schmeck B, Hocke AC, Rosseau S, Hammerschmidt S et al (2004) Nucleotide-binding oligomerization domain proteins are innate immune receptors for internalized Streptococcus pneumoniae. J Biol Chem 279(35):36426–36432

    Article  CAS  PubMed  Google Scholar 

  117. Iyer JK, Coggeshall KM (2011) Cutting edge: primary innate immune cells respond efficiently to polymeric peptidoglycan, but not to peptidoglycan monomers. J Immunol 186(7):3841–3845

    Article  CAS  PubMed  Google Scholar 

  118. Park JT, Uehara T (2008) How bacteria consume their own exoskeletons (turnover and recycling of cell wall peptidoglycan). Microbiol Mol Biol Rev 72(2):211–227, table of contents

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Meylan E, Tschopp J, Karin M (2006) Intracellular pattern recognition receptors in the host response. Nature 442(7098):39–44

    Article  CAS  PubMed  Google Scholar 

  120. Goodell EW, Schwarz U (1985) Release of cell wall peptides into culture medium by exponentially growing Escherichia coli. J Bacteriol 162(1):391–397

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Mauck J, Chan L, Glaser L (1971) Turnover of the cell wall of Gram-positive bacteria. J Biol Chem 246(6):1820–1827

    CAS  PubMed  Google Scholar 

  122. Hirata Y, Maeda S, Ohmae T, Shibata W, Yanai A, Ogura K et al (2006) Helicobacter pylori induces IkappaB kinase alpha nuclear translocation and chemokine production in gastric epithelial cells. Infect Immun 74(3):1452–1461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Maeda S, Yoshida H, Ogura K, Mitsuno Y, Hirata Y, Yamaji Y et al (2000) H. pylori activates NF-kappaB through a signaling pathway involving IkappaB kinases, NF-kappaB-inducing kinase, TRAF2, and TRAF6 in gastric cancer cells. Gastroenterology 119(1):97–108

    Article  CAS  PubMed  Google Scholar 

  124. 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

    Article  CAS  PubMed  Google Scholar 

  125. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. LeBlanc PM, Yeretssian G, Rutherford N, Doiron K, Nadiri A, Zhu L et al (2008) Caspase-12 modulates NOD signaling and regulates antimicrobial peptide production and mucosal immunity. Cell Host Microbe 3(3):146–157

    Article  CAS  PubMed  Google Scholar 

  127. Lee J, Tattoli I, Wojtal KA, Vavricka SR, Philpott DJ, Girardin SE (2009) pH-dependent internalization of muramyl peptides from early endosomes enables Nod1 and Nod2 signaling. J Biol Chem 284(35):23818–23829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Marina-Garcia N, Franchi L, Kim YG, Hu Y, Smith DE, Boons GJ et al (2009) Clathrin- and dynamin-dependent endocytic pathway regulates muramyl dipeptide internalization and NOD2 activation. J Immunol 182(7):4321–4327

    Article  CAS  PubMed  Google Scholar 

  129. Vavricka SR, Musch MW, Chang JE, Nakagawa Y, Phanvijhitsiri K, Waypa TS et al (2004) hPepT1 transports muramyl dipeptide, activating NF-kappaB and stimulating IL-8 secretion in human colonic Caco2/bbe cells. Gastroenterology 127(5):1401–1409

    Article  CAS  PubMed  Google Scholar 

  130. Ismair MG, Vavricka SR, Kullak-Ublick GA, Fried M, Mengin-Lecreulx D, Girardin SE (2006) hPepT1 selectively transports muramyl dipeptide but not Nod1-activating muramyl peptides. Can J Physiol Pharmacol 84(12):1313–1319

    Article  CAS  PubMed  Google Scholar 

  131. Fei YJ, Kanai Y, Nussberger S, Ganapathy V, Leibach FH, Romero MF et al (1994) Expression cloning of a mammalian proton-coupled oligopeptide transporter. Nature 368(6471):563–566

    Article  CAS  PubMed  Google Scholar 

  132. Nakamura N, Lill JR, Phung Q, Jiang Z, Bakalarski C, de Mazière A et al (2014) Endosomes are specialized platforms for bacterial sensing and NOD2 signalling. Nature 509(7499):240–244

    Article  CAS  PubMed  Google Scholar 

  133. Canton J, Schlam D, Breuer C, Gütschow M, Glogauer M, Grinstein S (2016) Calcium-sensing receptors signal constitutive macropinocytosis and facilitate the uptake of NOD2 ligands in macrophages. Nat Commun 7:11284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Kuehn MJ, Kesty NC (2005) Bacterial outer membrane vesicles and the host-pathogen interaction. Genes Dev 19(22):2645–2655

    Article  CAS  PubMed  Google Scholar 

  135. Kaparakis M, Turnbull L, Carneiro L, Firth S, Coleman HA, Parkington HC et al (2010) Bacterial membrane vesicles deliver peptidoglycan to NOD1 in epithelial cells. Cell Microbiol 12(3):372–385

    Article  CAS  PubMed  Google Scholar 

  136. Kesty NC, Mason KM, Reedy M, Miller SE, Kuehn MJ (2004) Enterotoxigenic Escherichia coli vesicles target toxin delivery into mammalian cells. EMBO J 23(23):4538–4549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Bielig H, Rompikuntal PK, Dongre M, Zurek B, Lindmark B, Ramstedt M et al (2011) NOD-like receptor activation by outer membrane vesicles from Vibrio cholerae non-O1 non-O139 strains is modulated by the quorum-sensing regulator HapR. Infect Immun 79(4):1418–1427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Laroui H, Yan Y, Narui Y, Ingersoll SA, Ayyadurai S, Charania MA et al (2011) L-Ala-γ-D-Glu-meso-diaminopimelic acid (DAP) interacts directly with leucine-rich region domain of nucleotide-binding oligomerization domain 1, increasing phosphorylation activity of receptor-interacting serine/threonine-protein kinase 2 and its interaction with nucleotide-binding oligomerization domain 1. J Biol Chem 286(35):31003–31013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Grimes CL, Ariyananda Lde Z, Melnyk JE, O’Shea EK (2012) The innate immune protein Nod2 binds directly to MDP, a bacterial cell wall fragment. J Am Chem Soc 134(33):13535–13537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Mo J, Boyle JP, Howard CB, Monie TP, Davis BK, Duncan JA (2012) Pathogen sensing by nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is mediated by direct binding to muramyl dipeptide and ATP. J Biol Chem 287(27):23057–23067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Wang YC, Westcott NP, Griffin ME, Hang HC (2019) Peptidoglycan metabolite photoaffinity reporters reveal direct binding to intracellular pattern recognition receptors and Arf GTPases. ACS Chem Biol 14(3):405–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J et al (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411(6837):599–603

    Article  CAS  PubMed  Google Scholar 

  143. McGovern DP, Hysi P, Ahmad T, van Heel DA, Moffatt MF, Carey A et al (2005) Association between a complex insertion/deletion polymorphism in NOD1 (CARD4) and susceptibility to inflammatory bowel disease. Hum Mol Genet 14(10):1245–1250

    Article  CAS  PubMed  Google Scholar 

  144. Van Limbergen J, Nimmo ER, Russell RK, Drummond HE, Smith L, Anderson NH et al (2007) Investigation of NOD1/CARD4 variation in inflammatory bowel disease using a haplotype-tagging strategy. Hum Mol Genet 16(18):2175–2186

    Article  PubMed  CAS  Google Scholar 

  145. van Heel DA, Ghosh S, Butler M, Hunt KA, Lundberg AM, Ahmad T et al (2005) Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn’s disease. Lancet 365(9473):1794–1796

    Article  PubMed  CAS  Google Scholar 

  146. Rivas MA, Beaudoin M, Gardet A, Stevens C, Sharma Y, Zhang CK et al (2011) Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 43(11):1066–1073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Watanabe T, Asano N, Murray PJ, Ozato K, Tailor P, Fuss IJ et al (2008) Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis. J Clin Invest 118(2):545–559

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Macho Fernandez E, Valenti V, Rockel C, Hermann C, Pot B, Boneca IG et al (2011) Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide. Gut 60(8):1050–1059

    Article  PubMed  CAS  Google Scholar 

  149. Barreau F, Meinzer U, Chareyre F, Berrebi D, Niwa-Kawakita M, Dussaillant M et al (2007) CARD15/NOD2 is required for Peyer’s patches homeostasis in mice. PLoS One 2(6):e523

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Penack O, Smith OM, Cunningham-Bussel A, Liu X, Rao U, Yim N et al (2009) NOD2 regulates hematopoietic cell function during graft-versus-host disease. J Exp Med 206(10):2101–2110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Biswas A, Liu YJ, Hao L, Mizoguchi A, Salzman NH, Bevins CL et al (2010) Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum. Proc Natl Acad Sci U S A 107(33):14739–14744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Geddes K, Rubino S, Streutker C, Cho JH, Magalhaes JG, Le Bourhis L et al (2010) Nod1 and Nod2 regulation of inflammation in the Salmonella colitis model. Infect Immun 78(12):5107–5115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Kim YG, Shaw MH, Warner N, Park JH, Chen F, Ogura Y et al (2011) Cutting edge: Crohn’s disease-associated Nod2 mutation limits production of proinflammatory cytokines to protect the host from Enterococcus faecalis-induced lethality. J Immunol 187(6):2849–2852

    Article  CAS  PubMed  Google Scholar 

  154. Adler J, Rangwalla SC, Dwamena BA, Higgins PD (2011) The prognostic power of the NOD2 genotype for complicated Crohn’s disease: a meta-analysis. Am J Gastroenterol 106(4):699–712

    Article  CAS  PubMed  Google Scholar 

  155. Ramanan D, Tang MS, Bowcutt R, Loke P, Cadwell K (2014) Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus. Immunity 41(2):311–324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Merger M, Viney JL, Borojevic R, Steele-Norwood D, Zhou P, Clark DA et al (2002) Defining the roles of perforin, Fas/FasL, and tumour necrosis factor alpha in T cell induced mucosal damage in the mouse intestine. Gut 51(2):155–163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Zanello G, Goethel A, Rouquier S, Prescott D, Robertson SJ, Maisonneuve C et al (2016) The cytosolic microbial receptor Nod2 regulates small intestinal crypt damage and epithelial regeneration following T cell-induced enteropathy. J Immunol 197(1):345–355

    Article  CAS  PubMed  Google Scholar 

  158. Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M et al (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449(7165):1003–1007

    Article  CAS  PubMed  Google Scholar 

  159. Nigro G, Rossi R, Commere PH, Jay P, Sansonetti PJ (2014) The cytosolic bacterial peptidoglycan sensor Nod2 affords stem cell protection and links microbes to gut epithelial regeneration. Cell Host Microbe 15(6):792–798

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Melbourne, VIC, Australia

    Maria Kaparakis-Liaskos

  2. Department of Immunology, University of Toronto, Toronto, ON, Canada

    Ashleigh Goethel & Dana J. Philpott

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  1. Maria Kaparakis-Liaskos
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  2. Ashleigh Goethel
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  3. Dana J. Philpott
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Correspondence to Dana J. Philpott .

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Editors and Affiliations

  1. Gastroenterology unit, Patient Area Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden

    Charlotte Hedin

  2. Montreal Heart Institute and Université de Montréal, Montréal, QC, Canada

    John D. Rioux

  3. School of Biological Sciences, Monash University, Clayton, VIC, Australia

    Mauro D'Amato

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Kaparakis-Liaskos, M., Goethel, A., Philpott, D.J. (2019). NOD1 and NOD2 and the Immune Response to Bacteria. In: Hedin, C., Rioux, J., D'Amato, M. (eds) Molecular Genetics of Inflammatory Bowel Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-28703-0_12

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