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The immunopathogenesis of sepsis

Abstract

Sepsis is a condition that results from a harmful or damaging host response to infection. Many of the components of the innate immune response that are normally concerned with host defences against infection can, under some circumstances, cause cell and tissue damage and hence multiple organ failure, the clinical hallmark of sepsis. Because of the high mortality of sepsis in the face of standard treatment, many efforts have been made to improve understanding of the dysregulation of the host response in sepsis. As a result, much has been learnt of the basic principles governing bacterial–host interactions, and new opportunities for therapeutic intervention have been revealed.

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Figure 1: Cell-surface recognition of lipopolysaccharide (LPS).
Figure 2: Sepsis disturbs the normal homeostatic balance between procoagulant and anticoagulant mechanisms.
Figure 3: Pathogenetic networks in shock.

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References

  1. Angus, D. C. et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 29, 1303–1310 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Alberti, C. et al. Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive Care Med. 28, 108–121 (2002).

    Article  PubMed  Google Scholar 

  3. Janeway, C. A. Jr & Medzhitov, R. Introduction: the role of innate immunity in the adaptive immune response. Semin. Immunol. 10, 349–350 (1998).

    Article  PubMed  Google Scholar 

  4. Seydel, U., Oikawa, M., Fukase, K., Kusumoto, S. & Brandenburg, K. Intrinsic conformation of lipid A is responsible for agonistic and antagonistic activity. Eur. J. Biochem. 267, 3032–3039 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Majcherczyk, P. A. et al. Digestion of Streptococcus pneumoniae cell walls with its major peptidoglycan hydrolase releases branched stem peptides carrying proinflammatory activity. J. Biol. Chem. 274, 12537–12543 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Morath, S., Geyer, A. & Hartung, T. Structure–function relationship of cytokine induction by lipoteichoic acid from Staphylococcus aureus. J. Exp. Med. 193, 393–397 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang, J. E. et al. Peptidoglycan and lipoteichoic acid from Staphylococcus aureus induce tumor necrosis factor alpha, interleukin 6 (IL-6), and IL-10 production in both T cells and monocytes in a human whole blood model. Infect. Immun. 68, 3965–3970 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lavoie, P. M., Thibodeau, J., Erard, F. & Sekaly, R. P. Understanding the mechanism of action of bacterial superantigens from a decade of research. Immunol. Rev. 168, 257–269 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Papageorgiou, A. C. & Acharya, K. R. Microbial superantigens: from structure to function. Trends Microbiol. 8, 369–375 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Kotb, M. Bacterial pyrogenic exotoxins as superantigens. Clin. Microbiol. Rev. 8, 411–426 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Norrby-Teglund, A. et al. Evidence for superantigen involvement in severe group A streptococcal tissue infections. J. Infect. Dis. 184, 853–860 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Muller-Alouf, H. et al. Pyrogenicity and cytokine-inducing properties of Streptococcus pyogenes superantigens: comparative study of streptococcal mitogenic exotoxin Z and pyrogenic exotoxin A. Infect. Immun. 69, 4141–4145 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Unnikrishnan, M. et al. The bacterial superantigen streptococcal mitogenic exotoxin Z is the major immunoactive agent of Streptococcus pyogenes. J. Immunol. 169, 2561–2569 (2002)

    Article  CAS  PubMed  Google Scholar 

  14. Dinges, M. M. & Schlievert, P. M. Role of T cells and gamma interferon during induction of hypersensitivity to lipopolysaccharide by toxic shock syndrome toxin 1 in mice. Infect. Immun. 69, 1256–1264 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Eaves-Pyles, T. et al. Flagellin, a novel mediator of salmonella-induced epithelial activation and systemic inflammation: IκBα degradation, induction of nitric oxide synthase, induction of proinflammatory mediators, and cardiovascular dysfunction. J. Immunol. 166, 1248–1260 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Herwald, H. et al. Activation of the contact-phase system on bacterial surfaces—a clue to serious complications in infectious diseases. Nature Med. 4, 298–302 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Sparwasser, T. et al. Bacterial DNA causes septic shock. Nature 386, 336–337 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Bauer, S. et al. Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc. Natl Acad. Sci. USA 98, 9237–9242 (2001).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wright, S. D., Ramos, R. A., Tobias, P. S., Ulevitch, R. J. & Mathison, J. C. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249, 1431–1433 (1990).

    Article  ADS  CAS  PubMed  Google Scholar 

  20. Pugin, J. et al. CD14 is a pattern recognition receptor. Immunity 1, 509–516 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Devitt, A. et al. Human CD14 mediates recognition and phagocytosis of apoptotic cells. Nature 392, 505–509 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Yu, B., Hailman, E. & Wright, S. D. Lipopolysaccharide binding protein and soluble CD14 catalyze exchange of phospholipids. J. Clin. Invest. 99, 315–324 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Landmann, R. et al. Increased circulating soluble CD14 is associated with high mortality in Gram-negative septic shock. J. Infect. Dis. 171, 639–644 (1995).

    Article  CAS  PubMed  Google Scholar 

  24. Leturcq, D. J. et al. Antibodies against CD14 protect primates from endotoxin-induced shock. J. Clin. Invest. 98, 1533–1538 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Aderem, A. & Ulevitch, R. J. Toll-like receptors in the induction of the innate immune response. Nature 406, 782–787 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Vasselon, T. & Detmers, P. A. Toll receptors: a central element in innate immune responses. Infect. Immun. 70, 1033 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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).

    Article  ADS  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  29. Opal, S. M. & Huber, Ch. Bench-to-bedside review: Toll-like receptors and their role in septic shock. Crit. Care 6, 125–136 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Takeuchi, O. et al. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 11, 443–451 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Hayashi, F. et al. The innate immune response to bacterial flagellin is mediated by Toll- like receptor 5. Nature 410, 1099–1103 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  32. Shimazu, R. et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J. Exp. Med. 189, 1777–1782 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nagai, Y. et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nature Immunol. 3, 667–672 (2002).

    Article  CAS  Google Scholar 

  34. Ozinsky, A. et al. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc. Natl Acad. Sci. USA 97, 13766–13771 (2000).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lorenz, E., Mira, J. P., Cornish, K. L., Arbour, N. C. & Schwartz, D. A. A novel polymorphism in the Toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect. Immun. 68, 6398–6401 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lorenz, E., Mira, J. P., Frees, K. L. & Schwartz, D. A. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch. Intern. Med. 162, 1028–1032 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Bowie, A. & O'Neill, L. A. The interleukin-1 receptor/Toll-like receptor superfamily: signal generators for pro-inflammatory interleukins and microbial products. J. Leukoc. Biol. 67, 508–514 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Werner, T. et al. A family of peptidoglycan recognition proteins in the fruit fly Drosophila melanogaster. Proc. Natl Acad. Sci. USA 97, 13772–13777 (2000).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liu, C., Xu, Z., Gupta, D. & Dziarski, R. Peptidoglycan recognition proteins: a novel family of four human innate immunity pattern recognition molecules. J. Biol. Chem. 276, 34686–34694 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Michel, T., Reichhart, J. M., Hoffmann, J. A. & Royet, J. Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein. Nature 414, 756–759 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  41. Gottar, M. et al. The Drosophila immune response against Gram-negative bacteria is mediated by a peptidoglycan recognition protein. Nature 416, 640–644 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  42. Ramet, M., Manfruelli, P., Pearson, A., Mathey-Prevot, B. & Ezekowitz, R. A. Functional genomic analysis of phagocytosis and identification of a Drosophila receptor for E. coli. Nature 416, 644–648 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  43. Choe, K. M., Werner, T., Stoven, S., Hultmark, D. & Anderson, K. V. Requirement for a peptidoglycan recognition protein (PGRP) in Relish activation and antibacterial immune responses in Drosophila. Science 296, 359–362 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  44. Bouchon, A., Dietrich, J. & Colonna, M. Inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J. Immunol. 164, 4991–4995 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Bouchon, A., Facchetti, F., Weigand, M. A. & Colonna, M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature 410, 1103–1107 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  47. 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).

    Article  CAS  PubMed  Google Scholar 

  48. Hampe, J. et al. Association of NOD2 (CARD 15) genotype with clinical course of Crohn's disease: a cohort study. Lancet 359, 1661–1665 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Dinarello, C. A. Proinflammatory and anti-inflammatory cytokines as mediators in the pathogenesis of septic shock. Chest 112, 321S–329S (1997).

    Article  CAS  PubMed  Google Scholar 

  50. Cohen, J. Adjunctive therapy in sepsis: a critical analysis of the clinical trial programme. Br. Med. Bull. 55, 212–226 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Yang, H., Wang, H. & Tracey, K. J. HMG-1 rediscovered as a cytokine. Shock 15, 247–253 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Wang, H. et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 285, 248–251 (1999).

    Article  CAS  PubMed  Google Scholar 

  53. Bozza, M. et al. Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis. J. Exp. Med. 189, 341–346 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Calandra, T. et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nature Med. 6, 164–170 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Calandra, T., Spiegel, L. A., Metz, C. N. & Bucala, R. Macrophage migration inhibitory factor is a critical mediator of the activation of immune cells by exotoxins of Gram-positive bacteria. Proc. Natl Acad. Sci. USA 95, 11383–11388 (1998).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  56. Calandra, T. et al. MIF as a glucocorticoid-induced modulator of cytokine production. Nature 377, 68–71 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  57. Bosisio, D. et al. Stimulation of toll-like receptor 4 expression in human mononuclear phagocytes by interferon-gamma: a molecular basis for priming and synergism with bacterial lipopolysaccharide. Blood 99, 3427–3431 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Levi, M. & ten Cate, H. Disseminated intravascular coagulation. N. Engl. J. Med. 341, 586–592 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Van der Poll, T., de Jonge, E., Levi, M. & van Deventer, S. J. Pathogenesis of DIC in sepsis. Sepsis 3, 103–110 (1999).

    Article  Google Scholar 

  60. Okajima, K. Regulation of inflammatory responses by natural anticoagulants. Immunol. Rev. 184, 258–274 (2002).

    Article  Google Scholar 

  61. Riewald, M., Petrovan, R. J., Donner, A., Mueller, B. M. & Ruf, W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296, 1880–1882 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  62. Faust, S. N. et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N. Engl. J. Med. 345, 408–416 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Hotchkiss, R. S. et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit. Care Med. 27, 1230–1251 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Hotchkiss, R. S. et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J. Immunol. 166, 6952–6963 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Hotchkiss, R. S. et al. Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc. Natl Acad. Sci. USA 96, 14541–14546 (1999).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  66. Döcke, W.-D. et al. Monocyte deactivation in septic patients: restoration by IFN-γ treatment. Nature Med. 3, 678–681 (1997).

    Article  PubMed  Google Scholar 

  67. Stuber, F. Effects of genomic polymorphisms on the course of sepsis: is there a concept for gene therapy? J. Am. Soc. Nephrol. 12(Suppl. 17), S60–S64 (2001).

    CAS  PubMed  Google Scholar 

  68. Landry, D. W. & Oliver, J. A. The pathogenesis of vasodilatory shock. N. Engl. J. Med. 345, 588–595 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Brealey, D. et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360, 219–223 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Rivers, E. et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N. Engl. J. Med. 345, 1368–1377 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Van den Berghe, G. et al. Intensive insulin therapy in critically ill patients. N. Engl. J. Med. 345, 1359–1367 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Annane, D. et al. Effects of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. J. Am. Med. Assoc. 288, 862–871 (2002).

    Article  CAS  Google Scholar 

  73. Bernard, G. R. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 344, 699–709 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Bochkov, V. N. et al. Protective role of phospholipid oxidation products in endotoxin-induced tissue damage. Nature 419, 77–81 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

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Cohen, J. The immunopathogenesis of sepsis. Nature 420, 885–891 (2002). https://doi.org/10.1038/nature01326

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