Beyond pattern recognition: five immune checkpoints for scaling the microbial threat

Abstract

Pattern recognition by the innate immune system enables the detection of microorganisms, but how the level of microbial threat is evaluated — a process that is crucial for eliciting measured antimicrobial responses with minimal inflammatory tissue damage — is less well understood. New evidence has shown that features of microbial viability can be detected by the immune system and thereby induce robust responses that are not warranted for dead microorganisms. Here, we propose five immune checkpoints that, as defined here, collectively determine the gravity of microbial encounters.

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Figure 1: Correlation of the microbial threat with inflammatory responses.
Figure 2: Sensing vita-PAMPs.
Figure 3: Detecting features of invasiveness.
Figure 4: The class and context of pattern recognition indicates the microbial threat level and dictates the nature and magnitude of the immune response.

References

  1. 1

    Janeway, C. A. Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989).

  2. 2

    Medzhitov, R., Preston-Hurlburt, P. & Janeway, C. A. Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397 (1997).

  3. 3

    Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J. M. & Hoffmann, J. A. The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973–983 (1996).

  4. 4

    Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

  5. 5

    Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

  6. 6

    Iwasaki, A. & Medzhitov, R. Regulation of adaptive immunity by the innate immune system. Science 327, 291–295 (2010).

  7. 7

    Inohara, N., Ogura, Y. & Nunez, G. Nods: a family of cytosolic proteins that regulate the host response to pathogens. Curr. Opin. Microbiol. 5, 76–80 (2002).

  8. 8

    Philpott, D. J. & Girardin, S. E. Nod-like receptors: sentinels at host membranes. Curr. Opin. Immunol. 22, 428–434 (2010).

  9. 9

    Yoneyama, M. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nature Immunol. 5, 730–737 (2004).

  10. 10

    Osorio, F. & Reis, E. S. C. Myeloid C-type lectin receptors in pathogen recognition and host defense. Immunity 34, 651–664 (2011).

  11. 11

    Kumar, H., Kawai, T. & Akira, S. Pathogen recognition by the innate immune system. Int. Rev. Immunol. 30, 16–34 (2011).

  12. 12

    Kawai, T. & Akira, S. TLR signaling. Semin. Immunol. 19, 24–32 (2007).

  13. 13

    Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell 10, 417–426 (2002).

  14. 14

    Picard, C., Casanova, J. L. & Puel, A. Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IκBα deficiency. Clin. Microbiol. Rev. 24, 490–497 (2011).

  15. 15

    Picard, C. et al. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine 89, 403–425 (2010).

  16. 16

    Fischer, A. Human primary immunodeficiency diseases. Immunity 27, 835–845 (2007).

  17. 17

    Bousfiha, A. et al. Primary immunodeficiencies of protective immunity to primary infections. Clin. Immunol. 135, 204–209 (2010).

  18. 18

    Vance, R. E., Isberg, R. R. & Portnoy, D. A. Patterns of pathogenesis: discrimination of pathogenic and nonpathogenic microbes by the innate immune system. Cell Host Microbe 6, 10–21 (2009).

  19. 19

    von Koenig, C. H., Finger, H. & Hof, H. Failure of killed Listeria monocytogenes vaccine to produce protective immunity. Nature 297, 233–234 (1982).

  20. 20

    Lauvau, G. et al. Priming of memory but not effector CD8 T cells by a killed bacterial vaccine. Science 294, 1735–1739 (2001).

  21. 21

    Varol, C., Zigmond, E. & Jung, S. Securing the immune tightrope: mononuclear phagocytes in the intestinal lamina propria. Nature Rev. Immunol. 10, 415–426 (2010).

  22. 22

    Goodridge, H. S. et al. Activation of the innate immune receptor Dectin-1 upon formation of a 'phagocytic synapse'. Nature 472, 471–475 (2011).

  23. 23

    Napolitani, G., Rinaldi, A., Bertoni, F., Sallusto, F. & Lanzavecchia, A. Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nature Immunol. 6, 769–776 (2005).

  24. 24

    Underhill, D. M. Collaboration between the innate immune receptors dectin-1, TLRs, and Nods. Immunol. Rev. 219, 75–87 (2007).

  25. 25

    Kasturi, S. P. et al. Programming the magnitude and persistence of antibody responses with innate immunity. Nature 470, 543–547 (2011).

  26. 26

    Detmer, A. & Glenting, J. Live bacterial vaccines – a review and identification of potential hazards. Microb. Cell Fact. 5, 23 (2006).

  27. 27

    Sander, L. E. et al. Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. Nature 474, 385–389 (2011).

  28. 28

    Pulendran, B. & Ahmed, R. Immunological mechanisms of vaccination. Nature Immunol. 12, 509–517 (2011).

  29. 29

    Galan, J. E. Common themes in the design and function of bacterial effectors. Cell Host Microbe 5, 571–579 (2009).

  30. 30

    Backert, S., Tegtmeyer, N. & Selbach, M. The versatility of Helicobacter pylori CagA effector protein functions: the master key hypothesis. Helicobacter 15, 163–176 (2010).

  31. 31

    Viboud, G. I. & Bliska, J. B. Yersinia outer proteins: role in modulation of host cell signaling responses and pathogenesis. Annu. Rev. Microbiol. 59, 69–89 (2005).

  32. 32

    Swanson, M. S. & Hammer, B. K. Legionella pneumophila pathogenesis: a fateful journey from amoebae to macrophages. Annu. Rev. Microbiol. 54, 567–613 (2000).

  33. 33

    Viala, J. et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nature Immunol. 5, 1166–1174 (2004).

  34. 34

    Brodsky, I. E. et al. A Yersinia effector protein promotes virulence by preventing inflammasome recognition of the type III secretion system. Cell Host Microbe 7, 376–387 (2010).

  35. 35

    Kofoed, E. M. & Vance, R. E. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 477, 592–595 (2011).

  36. 36

    Zhao, Y. et al. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477, 596–600 (2011).

  37. 37

    Freche, B., Reig, N. & van der Goot, F. G. The role of the inflammasome in cellular responses to toxins and bacterial effectors. Semin. Immunopathol. 29, 249–260 (2007).

  38. 38

    Gurcel, L., Abrami, L., Girardin, S., Tschopp, J. & van der Goot, F. G. Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival. Cell 126, 1135–1145 (2006).

  39. 39

    Hornung, V. et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458, 514–518 (2009).

  40. 40

    Rathinam, V. A. et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nature Immunol. 11, 395–402 (2010).

  41. 41

    Miao, E. A. et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf. Nature Immunol. 7, 569–575 (2006).

  42. 42

    Mariathasan, S. et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430, 213–218 (2004).

  43. 43

    Fontana, M. F. et al. Secreted bacterial effectors that inhibit host protein synthesis are critical for induction of the innate immune response to virulent Legionella pneumophila. PLoS Pathog. 7, e1001289 (2011).

  44. 44

    Boyer, L. et al. Pathogen-derived effectors trigger protective immunity via activation of the Rac2 enzyme and the IMD or Rip kinase signaling pathway. Immunity 35, 536–549 (2011).

  45. 45

    Miao, E. A. & Rajan, J. V. Salmonella and caspase-1: a complex interplay of detection and evasion. Front. Microbiol. 2, 85 (2011).

  46. 46

    Broz, P. et al. Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. J. Exp. Med. 207, 1745–1755 (2010).

  47. 47

    Mylonakis, E. & Calderwood, S. B. Infective endocarditis in adults. N. Engl. J. Med. 345, 1318–1330 (2001).

  48. 48

    Nolan, J. P. The role of intestinal endotoxin in liver injury: a long and evolving history. Hepatology 52, 1829–1835 (2010).

  49. 49

    Kelsall, B. Recent progress in understanding the phenotype and function of intestinal dendritic cells and macrophages. Mucosal Immunol. 1, 460–469 (2008).

  50. 50

    Eberl, G. & Boneca, I. G. Bacteria and MAMP-induced morphogenesis of the immune system. Curr. Opin. Immunol. 22, 448–454 (2010).

  51. 51

    Wen, L. et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455, 1109–1113 (2008).

  52. 52

    Aimanianda, V. et al. Surface hydrophobin prevents immune recognition of airborne fungal spores. Nature 460, 1117–1121 (2009).

  53. 53

    Hohl, T. M. et al. Aspergillus fumigatus triggers inflammatory responses by stage-specific β-glucan display. PLoS Pathog. 1, e30 (2005).

  54. 54

    Sudbery, P. E. Growth of Candida albicans hyphae. Nature Rev. Microbiol. 9, 737–748 (2011).

  55. 55

    Moyes, D. L. et al. A biphasic innate immune MAPK response discriminates between the yeast and hyphal forms of Candida albicans in epithelial cells. Cell Host Microbe 8, 225–235 (2010).

  56. 56

    d'Ostiani, C. F. et al. Dendritic cells discriminate between yeasts and hyphae of the fungus Candida albicans. Implications for initiation of T helper cell immunity in vitro and in vivo. J. Exp. Med. 191, 1661–1674 (2000).

  57. 57

    Cheng, S. C. et al. The dectin-1/inflammasome pathway is responsible for the induction of protective T-helper 17 responses that discriminate between yeasts and hyphae of Candida albicans. J. Leukoc. Biol. 90, 357–366 (2011).

  58. 58

    Gross, O. et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459, 433–436 (2009).

  59. 59

    Joly, S. et al. Cutting edge: Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome. J. Immunol. 183, 3578–3581 (2009).

  60. 60

    Lo, H. J. et al. Nonfilamentous C. albicans mutants are avirulent. Cell 90, 939–949 (1997).

  61. 61

    Peterson, M. M. et al. Apolipoprotein B is an innate barrier against invasive Staphylococcus aureus infection. Cell Host Microbe 4, 555–566 (2008).

  62. 62

    Coombes, J. L. & Powrie, F. Dendritic cells in intestinal immune regulation. Nature Rev. Immunol. 8, 435–446 (2008).

  63. 63

    Hu, W., Troutman, T. D., Edukulla, R. & Pasare, C. Priming microenvironments dictate cytokine requirements for T helper 17 cell lineage commitment. Immunity 35, 1010–1022 (2011).

  64. 64

    Torchinsky, M. B., Garaude, J., Martin, A. P. & Blander, J. M. Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation. Nature 458, 78–82 (2009).

  65. 65

    Hirotani, T. et al. The nuclear IκB protein IκBNS selectively inhibits lipopolysaccharide-induced IL-6 production in macrophages of the colonic lamina propria. J. Immunol. 174, 3650–3657 (2005).

  66. 66

    Monteleone, I., Platt, A. M., Jaensson, E., Agace, W. W. & Mowat, A. M. IL-10-dependent partial refractoriness to Toll-like receptor stimulation modulates gut mucosal dendritic cell function. Eur. J. Immunol. 38, 1533–1547 (2008).

  67. 67

    Smythies, L. E. et al. Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J. Clin. Invest. 115, 66–75 (2005).

  68. 68

    Taylor, B. C. et al. TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis. J. Exp. Med. 206, 655–667 (2009).

  69. 69

    Kruis, W. et al. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 53, 1617–1623 (2004).

  70. 70

    Kwon, H. K. et al. Generation of regulatory dendritic cells and CD4+Foxp3+ T cells by probiotics administration suppresses immune disorders. Proc. Natl Acad. Sci. USA 107, 2159–2164 (2010).

  71. 71

    Livingston, M., Loach, D., Wilson, M., Tannock, G. W. & Baird, M. Gut commensal Lactobacillus reuteri 100-23 stimulates an immunoregulatory response. Immunol. Cell Biol. 88, 99–102 (2010).

  72. 72

    Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

  73. 73

    Round, J. L. et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011).

  74. 74

    Sczesnak, A. et al. The genome of Th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment. Cell Host Microbe 10, 260–272 (2011).

  75. 75

    Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

  76. 76

    Pamer, E. G. Immune responses to commensal and environmental microbes. Nature Immunol. 8, 1173–1178 (2007).

  77. 77

    Macpherson, A. J. & Uhr, T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303, 1662–1665 (2004).

  78. 78

    Sato, A. et al. CD11b+ Peyer's patch dendritic cells secrete IL-6 and induce IgA secretion from naive B cells. J. Immunol. 171, 3684–3690 (2003).

  79. 79

    Benckert, J. et al. The majority of intestinal IgA+ and IgG+ plasmablasts in the human gut are antigen-specific. J. Clin. Invest. 121, 1946–1955 (2011).

  80. 80

    Lathrop, S. K. et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 478, 250–254 (2011).

  81. 81

    Varol, C. et al. Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity 31, 502–512 (2009).

  82. 82

    Francis, M. S., Wolf-Watz, H. & Forsberg, A. Regulation of type III secretion systems. Curr. Opin. Microbiol. 5, 166–172 (2002).

  83. 83

    Miao, E. A. et al. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nature Immunol. 11, 1136–1142 (2010).

  84. 84

    Monack, D. M., Mecsas, J., Bouley, D. & Falkow, S. Yersinia-induced apoptosis in vivo aids in the establishment of a systemic infection of mice. J. Exp. Med. 188, 2127–2137 (1998).

  85. 85

    Auerbuch, V. & Isberg, R. R. Growth of Yersinia pseudotuberculosis in mice occurs independently of Toll-like receptor 2 expression and induction of interleukin-10. Infect. Immun. 75, 3561–3570 (2007).

  86. 86

    Lemaitre, N., Sebbane, F., Long, D. & Hinnebusch, B. J. Yersinia pestis YopJ suppresses tumor necrosis factor α induction and contributes to apoptosis of immune cells in the lymph node but is not required for virulence in a rat model of bubonic plague. Infect. Immun. 74, 5126–5131 (2006).

  87. 87

    Netea, M. G. et al. Differential requirement for the activation of the inflammasome for processing and release of IL-1β in monocytes and macrophages. Blood 113, 2324–2335 (2009).

  88. 88

    Dinarello, C. A. A clinical perspective of IL-1β as the gatekeeper of inflammation. Eur. J. Immunol. 41, 1203–1217 (2011).

  89. 89

    Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).

  90. 90

    Green, D. R., Ferguson, T., Zitvogel, L. & Kroemer, G. Immunogenic and tolerogenic cell death. Nature Rev. Immunol. 9, 353–363 (2009).

  91. 91

    Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010).

  92. 92

    Kufer, T. A. & Sansonetti, P. J. NLR functions beyond pathogen recognition. Nature Immunol. 12, 121–128 (2011).

  93. 93

    Unterholzner, L. et al. IFI16 is an innate immune sensor for intracellular DNA. Nature Immunol. 11, 997–1004 (2010).

  94. 94

    Burckstummer, T. et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nature Immunol. 10, 266–272 (2009).

  95. 95

    Zhang, Z. et al. DDX1, DDX21, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in dendritic cells. Immunity 34, 866–878 (2011).

  96. 96

    Dangl, J. L. & Jones, J. D. Plant pathogens and integrated defence responses to infection. Nature 411, 826–833 (2001).

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Acknowledgements

We thank R. Medzhitov for critical reading of the manuscript. J.M.B. is a Burroughs Wellcome Investigator in the pathogenesis of infectious disease, and is also supported by grants from the US National Institute of Allergy and Infectious Diseases, the US National Institute of Diabetes and Digestive and Kidney Diseases, the American Cancer Society and the Hirschl Trust Fund. L.E.S. is supported by the German Research Foundation (DFG).

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Blander, J., Sander, L. Beyond pattern recognition: five immune checkpoints for scaling the microbial threat. Nat Rev Immunol 12, 215–225 (2012). https://doi.org/10.1038/nri3167

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