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Innate Sensors of Microbial Infection

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Abstract

The innate immune system utilizes multiple families of pattern-recognition receptors (PRRs) to protect the host from infection. Each of these families contributes certain elements to the complement of innate effector functions that is elicited during an infection. Here we review the families of PRRs and explore examples of their cooperativity.

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References

  1. Janeway CA, Jr: Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quantum Biol 54(Pt 1):1–13, 1989

    CAS  Google Scholar 

  2. Janeway CA, Jr, Medzhitov R: Innate immune recognition. Annu Rev Immunol 20:197–216, 2002

    PubMed  CAS  Google Scholar 

  3. Taylor PR, Martinez-Pomares L, Stacey M, Lin HH, Brown GD, Gordon S: Macrophage receptors and immune recognition. Annu Rev Immunol 23:901–944, 2005

    Article  PubMed  CAS  Google Scholar 

  4. Geijtenbeek TB, van Vliet SJ, Engering A, t Hart BA, van Kooyk Y: Self- and nonself-recognition by C-type lectins on dendritic cells. Annu Rev Immunol 22:33–54, 2004

    Article  PubMed  CAS  Google Scholar 

  5. Iwasaki A, Medzhitov R: Toll-like receptor control of the adaptive immune responses. Nat Immunol 5(10):987–995, 2004

    Article  PubMed  CAS  Google Scholar 

  6. Weiss DS, Raupach B, Takeda K, Akira S, Zychlinsky A: Toll-like receptors are temporally involved in host defense. J Immunol 172(7):4463–4469, 2004

    PubMed  CAS  Google Scholar 

  7. O'Brien AD, Rosenstreich DL, Scher I, Campbell GH, MacDermott RP, Formal SB: Genetic control of susceptibility to Salmonella typhimurium in mice: Role of the LPS gene. J Immunol 124(1):20–24, 1980

    PubMed  Google Scholar 

  8. Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, Matsui K, Tsujimura T, Takeda K, Fujita T, Takeuchi O, Akira S: Cell Type-specific involvement of RIG-I in antiviral response. Immunity 23(1):19–28, 2005

    Article  PubMed  CAS  Google Scholar 

  9. Roach JC, Glusman G, Rowen L, Kaur A, Purcell MK, Smith KD, Hood LE, Aderem A: The evolution of vertebrate Toll-like receptors. Proc Natl Acad Sci USA 102(27):9577–9582, 2005

    Article  PubMed  CAS  Google Scholar 

  10. Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, Ghosh S: A toll-like receptor that prevents infection by uropathogenic bacteria. Science 303(5663):1522–1526, 2004

    Article  PubMed  CAS  Google Scholar 

  11. Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS, Hieny S, Sutterwala FS, Flavell RA, Ghosh S, Sher A: TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308(5728):1626–1629, 2005

    Article  PubMed  CAS  Google Scholar 

  12. Edelmann KH, Richardson-Burns S, Alexopoulou L, Tyler KL, Flavell RA, Oldstone MB: Does Toll-like receptor 3 play a biological role in virus infections? Virology 322(2):231–238, 2004

    Article  PubMed  CAS  Google Scholar 

  13. Schroder M, Bowie AG: TLR3 in antiviral immunity: Key player or bystander? Trends Immunol 2005.

  14. Jiang Z, Georgel P, Du X, Shamel L, Sovath S, Mudd S, Huber M, Kalis C, Keck S, Galanos C, Freudenberg M, Beutler B: CD14 is required for MyD88-independent LPS signaling. Nat Immunol 6(6):565–570, 2005

    Article  PubMed  CAS  Google Scholar 

  15. Hoebe K, Georgel P, Rutschmann S, Du X, Mudd S, Crozat K, Sovath S, Shamel L, Hartung T, Zahringer U, Beutler B: CD36 is a sensor of diacylglycerides. Nature 433(7025):523–527, 2005

    Article  PubMed  CAS  Google Scholar 

  16. Miyake K, Yamashita Y, Ogata M, Sudo T, Kimoto M: RP105, a novel B cell surface molecule implicated in B cell activation, is a member of the leucine-rich repeat protein family. J Immunol 154(7):3333–3340, 1995

    PubMed  CAS  Google Scholar 

  17. Miyake K, Ogata H, Nagai Y, Akashi S, Kimoto M: Innate recognition of lipopolysaccharide by Toll-like receptor 4/MD-2 and RP105/MD-1. J Endotoxin Res 6(5):389–391, 2000

    Article  PubMed  CAS  Google Scholar 

  18. Divanovic S, Trompette A, Atabani SF, Madan R, Golenbock DT, Visintin A, Finberg RW, Tarakhovsky A, Vogel SN, Belkaid Y, Kurt-Jones EA, Karp CL: Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nat Immunol 6(6):571–578, 2005

    Article  PubMed  CAS  Google Scholar 

  19. Akira S, Takeda K: Toll-like receptor signalling. Nat Rev Immunol 4(7):499–511, 2004

    Article  PubMed  CAS  Google Scholar 

  20. Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T, Shimada N, Ohba Y, Takaoka A, Yoshida N, Taniguchi T: IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434(7034):772–777, 2005

    Article  PubMed  CAS  Google Scholar 

  21. Sato M, Hata N, Asagiri M, Nakaya T, Taniguchi T, Tanaka N: Positive feedback regulation of type I IFN genes by the IFN-inducible transcription factor IRF-7. FEBS Lett 441(1):106–110, 1998

    Article  PubMed  CAS  Google Scholar 

  22. Sato M, Suemori H, Hata N, Asagiri M, Ogasawara K, Nakao K, Nakaya T, Katsuki M, Noguchi S, Tanaka N, Taniguchi T: Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction. Immunity 13(4):539–548, 2000

    Article  PubMed  CAS  Google Scholar 

  23. Izaguirre A, Barnes BJ, Amrute S, Yeow WS, Megjugorac N, Dai J, Feng D, Chung E, Pitha PM, Fitzgerald-Bocarsly P: Comparative analysis of IRF and IFN-alpha expression in human plasmacytoid and monocyte-derived dendritic cells. J Leukoc Biol 74(6):1125–1138, 2003

    Article  PubMed  CAS  Google Scholar 

  24. Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, Kano S, Honda K, Ohba Y, Mak TW, Taniguchi T: Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434(7030):243–249, 2005

    Article  PubMed  CAS  Google Scholar 

  25. Yamamoto M, Yamazaki S, Uematsu S, Sato S, Hemmi H, Hoshino K, Kaisho T, Kuwata H, Takeuchi O, Takeshige K, Saitoh T, Yamaoka S, Yamamoto N, Yamamoto S, Muta T, Takeda K, Akira S: Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IkappaBzeta. Nature 430(6996):218–222, 2004

    Article  PubMed  CAS  Google Scholar 

  26. Franzoso G, Bours V, Azarenko V, Park S, Tomita-Yamaguchi M, Kanno T, Brown K, Siebenlist U: The oncoprotein Bcl-3 can facilitate NF-kappa B-mediated transactivation by removing inhibiting p50 homodimers from select kappa B sites. Embo J 12(10):3893–3901, 1993

    PubMed  CAS  Google Scholar 

  27. Motoyama M, Yamazaki S, Eto-Kimura A, Takeshige K, Muta T: Positive and negative regulation of nuclear factor-kappaB-mediated transcription by IkappaB-zeta, an inducible nuclear protein. J Biol Chem 280(9):7444–7451, 2005

    PubMed  CAS  Google Scholar 

  28. Hirotani T, Lee PY, Kuwata H, Yamamoto M, Matsumoto M, Kawase I, Akira S, Takeda K: The nuclear IkappaB protein IkappaBNS selectively inhibits lipopolysaccharide-induced IL-6 production in macrophages of the colonic lamina propria. J Immunol 174(6):3650–3657, 2005

    PubMed  CAS  Google Scholar 

  29. Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, Ogura Y, Kawasaki A, Fukase K, Kusumoto S, Valvano MA, Foster SJ, Mak TW, Nunez G, Inohara N: An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol 4(7):702–707, 2003

    Article  PubMed  CAS  Google Scholar 

  30. Girardin SE, Boneca IG, Carneiro LA, Antignac A, Jehanno M, Viala J, Tedin K, Taha MK, Labigne A, Zahringer U, Coyle AJ, DiStefano PS, Bertin J, Sansonetti PJ, Philpott DJ: Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science 300(5625):1584–1587, 2003

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  32. Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, Fukase K, Inamura S, Kusumoto S, Hashimoto M, Foster SJ, Moran AP, Fernandez-Luna JL, Nunez G: Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J Biol Chem 278(8):5509–5512, 2003

    CAS  Google Scholar 

  33. Barnich N, Aguirre JE, Reinecker HC, Xavier R, Podolsky DK: Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor-ΚB activation in muramyl dipeptide recognition. J Cell Biol 170(1):21–26, 2005

    Article  PubMed  CAS  Google Scholar 

  34. Fritz JH, Girardin SE, Fitting C, Werts C, Mengin-Lecreulx D, Caroff M, Cavaillon JM, Philpott DJ, Adib-Conquy M: Synergistic stimulation of human monocytes and dendritic cells by Toll-like receptor 4 and NOD1- and NOD2-activating agonists. Eur J Immunol 2005.

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

    Article  PubMed  CAS  Google Scholar 

  36. Girardin SE, Tournebize R, Mavris M, Page AL, Li X, Stark GR, Bertin J, DiStefano PS, Yaniv M, Sansonetti PJ, Philpott DJ: CARD4/Nod1 mediates NF-kappaB and JNK activation by invasive Shigella flexneri. EMBO Rep 2(8):736–742, 2001

    Article  PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

  38. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, Flavell RA: Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307(5710):731–734, 2005

    Article  PubMed  CAS  Google Scholar 

  39. Osada Y, Mitsuyama M, Une T, Matsumoto K, Otani T, Satoh M, Ogawa H, Nomoto K: Effect of L18-MDP(Ala), a synthetic derivative of muramyl dipeptide, on nonspecific resistance of mice to microbial infections. Infect Immun 37(1):292–300, 1982

    PubMed  CAS  Google Scholar 

  40. Eizuru Y, Nakagawa N, Hamasuna R, Minamishima Y: Protective effect of MDP-Lys(L18), a synthetic derivative of muramyldipeptide, on murine cytomegalovirus infection. Nat Immunol 11(4):225–236, 1992

    CAS  Google Scholar 

  41. Nau GJ, Richmond JF, Schlesinger A, Jennings EG, Lander ES, Young RA: Human macrophage activation programs induced by bacterial pathogens. Proc Natl Acad Sci USA 99(3):1503–1508, 2002

    Article  PubMed  CAS  Google Scholar 

  42. Todate A, Suda T, Kuwata H, Chida K, Nakamura H: Muramyl dipeptide-Lys stimulates the function of human dendritic cells. J Leukoc Biol 70(5):723–729, 2001

    PubMed  CAS  Google Scholar 

  43. Uehori J, Fukase K, Akazawa T, Uematsu S, Akira S, Funami K, Shingai M, Matsumoto M, Azuma I, Toyoshima K, Kusumoto S, Seya T: Dendritic cell maturation induced by muramyl dipeptide (MDP) derivatives: monoacylated MDP confers TLR2/TLR4 activation. J Immunol 174(11):7096–7103, 2005

    PubMed  CAS  Google Scholar 

  44. van Heel DA, Ghosh S, Butler M, Hunt K, Foxwell BM, Mengin-Lecreulx D, Playford RJ: Synergistic enhancement of Toll-like receptor responses by NOD1 activation. Eur J Immunol 2005.

  45. Netea MG, Ferwerda G, de Jong DJ, Jansen T, Jacobs L, Kramer M, Naber TH, Drenth JP, Girardin SE, Kullberg BJ, Adema GJ, Van der Meer JW: Nucleotide-binding oligomerization domain-2 modulates specific TLR pathways for the induction of cytokine release. J Immunol 174(10):6518–6523, 2005

    PubMed  CAS  Google Scholar 

  46. Watanabe T, Kitani A, Murray PJ, Strober W: NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol 5(8):800–808, 2004

    Article  PubMed  CAS  Google Scholar 

  47. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T: The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5(7):730–737, 2004

    Article  PubMed  CAS  Google Scholar 

  48. Sumpter R, Jr, Loo YM, Foy E, Li K, Yoneyama M, Fujita T, Lemon SM, Gale M, Jr: Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J Virol, 79(5):2689–2699, 2005

    Article  PubMed  CAS  Google Scholar 

  49. Breiman A, Grandvaux N, Lin R, Ottone C, Akira S, Yoneyama M, Fujita T, Hiscott J, Meurs EF: Inhibition of RIG-I-dependent signaling to the interferon pathway during hepatitis C virus expression and restoration of signaling by IKKepsilon. J Virol 79(7):3969–3978, 2005

    Article  PubMed  CAS  Google Scholar 

  50. Andrejeva J, Childs KS, Young DF, Carlos TS, Stock N, Goodbourn S, Randall RE: The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter. Proc Natl Acad Sci USA 101(49):17264–17269, 2004

    Article  PubMed  CAS  Google Scholar 

  51. Balachandran S, Thomas E, Barber GN: A FADD-dependent innate immune mechanism in mammalian cells. Nature 432(7015):401–405, 2004

    Article  PubMed  CAS  Google Scholar 

  52. Gantner BN, Simmons RM, Canavera SJ, Akira S, Underhill DM: Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J Exp Med 197(9):1107–1117, 2003

    Article  PubMed  CAS  Google Scholar 

  53. Underhill DM, Rossnagle E, Lowell CA, Simmons RM: Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production. Blood 106:2543–2550, 2005.

    Google Scholar 

  54. Rogers NC, Slack EC, Edwards AD, Nolte MA, Schulz O, Schweighoffer E, Williams DL, Gordon S, Tybulewicz VL, Brown GD, Reis ESC: Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22(4):507–517, 2005

    Article  PubMed  CAS  Google Scholar 

  55. Geijtenbeek TB, Van Vliet SJ, Koppel EA, Sanchez-Hernandez M, Vandenbroucke-Grauls CM, Appelmelk B, Van Kooyk Y: Mycobacteria target DC-SIGN to suppress dendritic cell function. J Exp Med 197(1):7–17, 2003

    Article  PubMed  CAS  Google Scholar 

  56. Bergman MP, Engering A, Smits HH, van Vliet SJ, van Bodegraven AA, Wirth HP, Kapsenberg ML, Vandenbroucke-Grauls CM, van Kooyk Y, Appelmelk BJ: Helicobacter pylori modulates the T helper cell 1/T helper cell 2 balance through phase-variable interaction between lipopolysaccharide and DC-SIGN. J Exp Med 200(8):979–990, 2004

    Article  PubMed  CAS  Google Scholar 

  57. Hamerman JA, Tchao NK, Lowell CA, Lanier LL: Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. Nat Immunol 6(6):579–586, 2005

    Article  PubMed  CAS  Google Scholar 

  58. 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. Nat Immunol 6(8):769–776, 2005

    Article  PubMed  CAS  Google Scholar 

  59. Gautier G, Humbert M, Deauvieau F, Scuiller M, Hiscott J, Bates EE, Trinchieri G, Caux C, Garrone P: A type I interferon autocrine-paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells. J Exp Med 201(9):1435–1446, 2005

    Article  PubMed  CAS  Google Scholar 

  60. Tabeta K, Georgel P, Janssen E, Du X, Hoebe K, Crozat K, Mudd S, Shamel L, Sovath S, Goode J, Alexopoulou L, Flavell RA, Beutler B: Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc Natl Acad Sci USA 101(10):3516–3521, 2004

    Article  PubMed  CAS  Google Scholar 

  61. Krug A, French AR, Barchet W, Fischer JA, Dzionek A, Pingel JT, Orihuela MM, Akira S, Yokoyama WM, Colonna M: TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity 21(1):107–119, 2004

    Article  PubMed  CAS  Google Scholar 

  62. Sato A, Iwasaki A: Induction of antiviral immunity requires Toll-like receptor signaling in both stromal and dendritic cell compartments. Proc Natl Acad Sci USA 101(46):16274–16279, 2004

    Article  PubMed  CAS  Google Scholar 

  63. O'Connell RM, Vaidya SA, Perry AK, Saha SK, Dempsey PW, Cheng G: Immune activation of type I IFNs by Listeria monocytogenes occurs independently of TLR4, TLR2, and receptor interacting protein 2 but involves TNFR-associated NF kappa B kinase-binding kinase 1. J Immunol 174(3):1602–1607, 2005

    PubMed  Google Scholar 

  64. Stockinger S, Reutterer B, Schaljo B, Schellack C, Brunner S, Materna T, Yamamoto M, Akira S, Taniguchi T, Murray PJ, Muller M, Decker T: IFN regulatory factor 3-dependent induction of type I IFNs by intracellular bacteria is mediated by a TLR- and Nod2-independent mechanism. J Immunol 173(12):7416–7425, 2004

    PubMed  CAS  Google Scholar 

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  1. HHMI and Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut

    Diana C. Hargreaves & Ruslan Medzhitov

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  1. Diana C. Hargreaves
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Hargreaves, D.C., Medzhitov, R. Innate Sensors of Microbial Infection. J Clin Immunol 25, 503–510 (2005). https://doi.org/10.1007/s10875-005-8065-4

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