Log in

Immune Aspects of Sepsis and Hope for New Therapeutics

  • Sepsis (J Russell, Section Editor)
  • Published:
Current Infectious Disease Reports Aims and scope Submit manuscript

Abstract

Marked alterations of the innate and adaptive immune response follow invasive infection and generalized inflammatory states. If left unchecked, this state of immune dysregulation contributes to a myriad of maladaptive cellular responses that culminate in multiple organ dysfunction, septic shock, and lethality. The molecular details of the cell-signaling networks that underlie the pathophysiology of systemic inflammation and sepsis are now increasingly well understood. While a vigorous and effective immune response to invasive pathogens is essential for microbial clearance and host survival, nonresolving, generalized inflammation can induce diffuse endovascular damage, increased capillary permeability, coagulopathy, and widespread tissue damage. Current evidence indicates that a state of relative immune suppression often accompanies sepsis and might provide novel therapeutic options in some patients. An expanding number of potential therapeutic options are now in clinical development to reestablish control and promote resolution over sepsis-induced systemic inflammation and organ dysfunction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. van der Poll T, Opal SM. Host-pathogen interactions in sepsis. Lancet Infect Dis. 2008;8:32–43.

    Article  PubMed  Google Scholar 

  2. Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a Primer. Crit Care Med. 2009;37(1):291–304.

    Article  PubMed  CAS  Google Scholar 

  3. •• **ao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured humans. J Exp Med. 2011. doi:10.1084/jem.20111354. This large study clearly demonstrates that the genes altered in acute systemic inflammation following severe injury follow similar patterns of upregulation and down regulation in patients that survive and those that do not survive. The differences in gene expression between survivors and non-survivors are primarily quantitative and not qualitative differences.

  4. • Netea MG, van der Meer JWM. Immunodeficiency and genetic defects of pattern recognition receptors. N Engl J Med. 2011;464(1):60–70. This is an excellent review of the current state of knowledge about pattern recognition receptors, their microbial ligands, and the innate immune response to invasive pathogens.

    Google Scholar 

  5. Rathinam VAK, Jiang Z, Waggoner SN, et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol. 2010;11(5):395–403.

    Article  PubMed  CAS  Google Scholar 

  6. Littman DR, Rudensky AY. Th17 and regulatory T cells in mediating and restraining inflammation. Cell. 2010;140:845–58.

    Article  PubMed  CAS  Google Scholar 

  7. Akira S, Takeda K. Toll-like receptor signaling. Nat Rev Immunol. 2004;4:499–511.

    Article  PubMed  CAS  Google Scholar 

  8. Beutler B. Inferences, questions and possibilities in toll-like receptor signaling. Nature. 2004;430:257–63.

    Article  PubMed  CAS  Google Scholar 

  9. Visvanathan K, Charles A, Bannan J, Pugach P, Kashfi K, Zabriskie J. Inhibition of bacterial superantigens by peptides and antibodies. Infect Immun. 2001;69:875–84.

    Article  PubMed  CAS  Google Scholar 

  10. • Arad G, Levy R, Nasie I, et al. Binding of superantigen toxins into the CD28 homodimer interface is essential for induction of cytokine genes that mediate lethal shock. PLoS Biology. 2011;9:e1001149. This study elucidates the mechanism by which superantigens trigger the release of inflammatory cytokines resulting in septic shock.

    Article  PubMed  CAS  Google Scholar 

  11. Sriskandan S, Ferguson M, Elliot V, Faulkner L, Cohen J. Human intravenous immunoglobulin for experimental streptococcal toxic shock: bacterial clearance and modulation of inflammation. J Antimicrob Chemother. 2006;58(1):117–24.

    Article  PubMed  CAS  Google Scholar 

  12. Levi M, Opal SM. Coagulation abnormalities in critically ill patients. Crit Care. 2006;10:222–8.

    Article  PubMed  Google Scholar 

  13. Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science. 2002;296(5574):1880–2.

    Article  PubMed  CAS  Google Scholar 

  14. Coughlin SR. Thrombin signaling and protease-activated receptors. Nature. 2000;407(6801):258–64.

    Article  PubMed  CAS  Google Scholar 

  15. Tressel SL, Kaneider NC, Foley C, et al. A matrix metalloprotease-PAR1 system regulates vascular integrity, systemic inflammation and death in sepsis. EMBO Mol Med. 2011;3:1–15.

    Article  Google Scholar 

  16. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348:138–50.

    Article  PubMed  CAS  Google Scholar 

  17. • Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA. Tilting toward immunosuppression. Nat Med. 2009;15(5):496–7. This is a superb review of the problem of sepsis-induced immune suppression and the potential therapeutic options to restore immune function in these vulnerable patients.

    Article  PubMed  CAS  Google Scholar 

  18. Hotchkiss RS, Nicholson DW. Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol. 2006;6:813–22.

    Article  PubMed  CAS  Google Scholar 

  19. Hotchkiss RS, Opal SM. Immunotherapy for sepsis-A new approach against an ancient foe. N Engl J Med. 2010;361(1):87–9.

    Article  Google Scholar 

  20. •• Boomer JS, To K, Chang KC, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011;306(23):2594–605. This study provides compelling pathologic and immunologic evidence that sepsis-induced immune suppression is commonplace in septic patients and the dominant finding in human lethal septic shock.

    Article  PubMed  CAS  Google Scholar 

  21. Rauch PJ, Chudnovskiy A, Robbins CS, et al. Innate response activator B cells protect against microbial sepsis. Science. 2012. doi:10.1126/science.1215173.

  22. Newell MK, Tobin RP, Cabrera JH, et al. TLR-mediated B cell activation results in ectopic CLIP expression that promotes B cell-dependent inflammation. J Leuk Biol. 2010;88:779–89.

    Article  CAS  Google Scholar 

  23. •• Nathan C, Ding A. Non-resolving inflammation. Cell. 2010;140:871–82. This is an excellent review of the critical elements that regulate the host response to human septic and sterile inflammatory processes. The mechanisms of immune and tissue-specific restoration of structure and function are examined in detail.

    Article  PubMed  CAS  Google Scholar 

  24. Jiang H, Chess L. Regulation of immune responses by T cells. N Engl J Med. 2006;354(11):1166–76.

    Article  PubMed  CAS  Google Scholar 

  25. Kasten KR, Tschop J, Adediran SG, Hideman DA, Caldwell CC. T cells are potent early mediators of the host response to sepsis. Shock. 2010;34(4):327–36.

    Article  PubMed  CAS  Google Scholar 

  26. Spite M, Serhan CN. Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins. Circ Res. 2010;107:1170–84.

    Article  PubMed  CAS  Google Scholar 

  27. Serhan CN, Savill J. Resolution of inflammation: the beginning programs the end. Nat Immunol. 2005;6:1191–7.

    Article  PubMed  CAS  Google Scholar 

  28. Schwab JM, Chiang N, Arita M, Serhan CN. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 2007; 869-74.

  29. • Ballina-Rosas M, Olofsson PS, Ochanni M, et al. Acetylcholine-synthesizing T Cells relay neural signals in a vagus nerve circuit. Science. 2011;334:98–101. This work points out the intricate interactions between Vagus nerve signals and anti-inflammatory signals within the spleen that regulate cellular immune function.

    Article  Google Scholar 

  30. • Wong CHY, Jenne CN, Lee W-Y, Léger C, Kubes P. Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science. 2011;334:101–5. This remarkable study identifies the role of the sympathetic nervous system in regulating the function of NKT cells and the important contribution of these uncommon T cells to bacterial clearance.

    Article  PubMed  CAS  Google Scholar 

  31. Mattsby-Baltzer I, Bergstrom T, McCrea K, et al. Affinity aphaeresis for treatment of bacteremia caused by Staphylococcus aureus and/or methicillin-resistant S. aureus (MRSA). J Microbiol Biotechnol. 2011;21(6):659–64.

    PubMed  Google Scholar 

  32. • Cruz DN, Perazella MA, Bellomo R, et al. Effectiveness of Polymyxin B-immobilized fiber column in sepsis: a systematic review. Crit Care. 2007;11:R47. This is a well performed meta-analysis of the randomized and non-randomized studies of the Polymyxin B immobilized filter. These results are the basis for the need for adequately powered, randomized, controlled clinical trial.

    Article  PubMed  Google Scholar 

  33. Cruz DN, Antonelli M, Fumagalli R, et al. Early use of polymyxin B hemoperfusion in abdominal septic shock, the EUPHAS randomized controlled trial. JAMA. 2009;301:2445–52.

    Article  PubMed  CAS  Google Scholar 

  34. Poelstra K, Bakker WW, Klok PA, et al. Dephosphorylation of endotoxin by alkaline phophatase in vivo. Am J Pathol. 1997;151:1163–9.

    PubMed  CAS  Google Scholar 

  35. Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol. 2009;27:229–65.

    Article  PubMed  CAS  Google Scholar 

  36. Verweij WR, Bentala H, van der Vlag AH, et al. Protection against an Escherichia coli- induced sepsis by alkaline phosphatase in mice. Shock. 2004;22:174–9.

    Article  PubMed  CAS  Google Scholar 

  37. Van Veen SQ, van Vliet AK, Wulferink M, et al. Bovine intestinal alkaline phosphatase attenuates the inflammatory response in secondary peritonitis in mice. Infect Immun. 2005;73:4309–14.

    Article  PubMed  Google Scholar 

  38. Heemskerk S, Masereeuw R, Moesker O, et al. Alkaline phosphatase treatment improves renal function in severe sepsis or septic shock patients. Crit Care Med. 2009;37:417–23.

    Article  PubMed  CAS  Google Scholar 

  39. • Pickkers P, Heemskerk S, Schouten J, et al. Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial. Crit Care. 2012;16:R14. This recently completed trial of alkaline phosphatase suggests that the benefit may be due to nephroprotective properties.

    Article  PubMed  Google Scholar 

  40. Teleman D, Chung CS, Ayala A, et al. AB103, a CD28 antagonist peptide: a new therapeutic agent in a model of severe sepsis. Crit Care. 2011;15(3):35.

    Article  Google Scholar 

  41. Rice TW, Wheeler AP, Morris PE, et al. Safety and efficacy of affinity-purified, anti-tumor necrosis factor-alpha, ovine Fab for injection (CytoFab) in severe sepsis. Crit Care Med. 2006;34:2271–81.

    Article  PubMed  CAS  Google Scholar 

  42. Yang H, Feldser H, Zhang W, et al. SIRT1 activators promote p65 deacetylation and suppress TNFα stimulated NF-κB activation. Abstract presented at the 2011 ASBMB Meeting in Washington D.C. in April 2011.

  43. Effect of Multiple Dose Levels of SRT2379 on Endotoxin-Induced Inflammation. Available at http://clinicaltrials.gov/ct2/show/NCT01416376. Accessed 11 April 2012.

  44. Zingarelli B, Cook JA. Peroxisome proliferator-activated receptor-gamma is a new therapeutic target in sepsis and inflammation. Shock. 2005;23:393–9.

    Article  PubMed  CAS  Google Scholar 

  45. Collin M, Murch O, Thiemermann C. Peroxisome proliferator-activated receptor-gamma antagonists GW9662 and T0070907 reduce the protective effects of lipopolysaccharide preconditioning against organ failure caused by endotoxemia. Crit Care Med. 2006;34:1131–8.

    Article  PubMed  CAS  Google Scholar 

  46. Kaplan JM, Denenberg A, Monaco M, et al. Changes in peroxisome proliferator-activated receptor-gamma activity in children with septic shock. Intensive Care Med. 2010;36:123–30.

    Article  PubMed  CAS  Google Scholar 

  47. Kapoor A, Shintani Y, Collino M, et al. Protective role of peroxisome proliferator-activated receptor-β/б in septic shock. Am J Respir Crit Care Med. 2010;182:1506–15.

    Article  PubMed  CAS  Google Scholar 

  48. • Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa activated in adults with septic shock. N Engl J Med. 2012;366:2055–64. This follow up study with recombinant human activated protein C failed to replicate improved survival in treated patients as observed in the original phase 3 trial. This drug has been taken off the market as a result of this study.

    Article  PubMed  CAS  Google Scholar 

  49. Mohri M, Sugimoto E, Sata M, et al. The inhibitory effect of recombinant human soluble thrombomodulin on initiation and extension of coagulation–a comparison with other anticoagulants. Thromb Haemost. 1999;82:1687–93.

    PubMed  CAS  Google Scholar 

  50. Saito H, Maruyama I, Shimazaki S, et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost. 2007;5:31–41.

    Article  PubMed  CAS  Google Scholar 

  51. Bhole D, Stahl GL. Therapeutic potential of targeting the complement cascade in critical care medicine. Crit Care Med. 2003;31(1 Suppl):S97–104.

    Article  PubMed  CAS  Google Scholar 

  52. Guo RF, Riedemann NC, Ward PA. Role of C5a-C5aR interaction in sepsis. Shock. 2004;21:1–7.

    Article  PubMed  Google Scholar 

  53. • Taylor FB, Kinasewitz GT, Lupu F. Pathophysiology, staging and therapy of severe sepsis in baboon models. J Cell Mol Med. 2012;16(4):672–82. This recently completed animal model of sepsis elucidates a second stage in sepsis whereby organ failure may be mediated by complement activation.

    Article  PubMed  CAS  Google Scholar 

  54. Silasi-Mansat R, Zhu H, Popescu NI, et al. Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis. Blood. 2010;116:1002–10.

    Article  PubMed  CAS  Google Scholar 

  55. Czermak BJ, Sarma V, Pierson CL, et al. Protective effects of C5a blockade in sepsis. Nat Med. 1999;5:788–92.

    Article  PubMed  CAS  Google Scholar 

  56. Igonin AA, Protsenko DN, Gennadiy GM, et al. C1-esterase inhibitor infusion increases survival rates for patients with sepsis. Crit Care Med. 2012;40:770–7.

    Article  PubMed  CAS  Google Scholar 

  57. Weaver JG, Rouse MS, Steckelberg JM, Badley AD. Improved survival in experimental sepsis with an orally administered inhibitor of apoptosis. FASEB J. 2004;18:1185–91.

    Article  PubMed  CAS  Google Scholar 

  58. Unsinger J, McGlynn M, Kasten KR, et al. IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol. 2010;184:3768–79.

    Article  PubMed  CAS  Google Scholar 

  59. Inoue S, Unsinger J, Davis CG, et al. IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction and improves survival in sepsis. J Immunol. 201;184 (3):1401-1409.

  60. Brahmamdam P, Inoue S, Unsinger J, Chang KC, McDunn JE, Hotchkiss RS. Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis. J Leukoc Biol. 2010;88:233–40.

    Article  PubMed  CAS  Google Scholar 

  61. Albring JC, Sandau MM, Rapaport AS, et al. Targeting of B and T lymphocyte associated (BTLA) prevents graft-versus-host disease without global immunosuppression. J Exp Med. 2010;207(12):2551–9.

    Article  PubMed  CAS  Google Scholar 

  62. Zhao G, ** H, Li J, et al. PyNTTTTGT prototype oligonucleotide IMT504, a novel effective adjuvant of the FMDV DNA vaccine. Viral Immunol. 2009;22(2):131–8.

    Article  PubMed  CAS  Google Scholar 

  63. Laporte R, Kohan A, Heitzmann J, et al. Pharmacological characterization of FE 202158, a novel, potent, selective, and short acting peptidic vasopressin V1a receptor full agonist for the treatment of vasodilatory hypotension. JPET. 2011;337(3):786–96.

    Article  CAS  Google Scholar 

  64. • Cribbs S, Matthay MA, Martin GS. Stem cells in sepsis and acute lung injury. Crit Care Med. 2010;38:2379–85. An excellent review of the multiple mechanisms of action of adult human stem cells. The paper further summarizes the experience to date with adult stem cells in animal models of sepsis and acute lung injury.

    Article  PubMed  Google Scholar 

  65. Mei SHJ, Haitsma JJ, Dos Santos CC, et al. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med. 2010;182:1047–57.

    Article  PubMed  CAS  Google Scholar 

  66. Krasnodembskaya A, Samarani G, Song Y, et al. Human mesenchymal stem cells reduce mortality and bacteremia in gram negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes. Am J Physiol Lung Cell Mol Physiol 2012; in press.

Download references

Disclosure

Dr. S. Opal has served as a consultant for Medimmune, Biotest, and Arsanis, received grant support for his institution fromAstra-Zenaca, Agennix, Asahi Kasel, David Horn LLC, Baxter, and Sirtris, and has served on data- and safety-monitoring boards for Sangart, Spectral Diagnostics, and Atoxio. Dr. S. LaRosa has served as a consultant for Ex Thera Medical and Agennix AG.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Steven M. Opal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

LaRosa, S.P., Opal, S.M. Immune Aspects of Sepsis and Hope for New Therapeutics. Curr Infect Dis Rep 14, 474–483 (2012). https://doi.org/10.1007/s11908-012-0276-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11908-012-0276-2

Keywords

Navigation