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The immunopathology of sepsis and potential therapeutic targets

Key Points

  • Sepsis is a life-threatening organ dysfunction that is caused by a dysregulated host response to infection.

  • The sepsis-associated host response is characterized by concurrent excessive inflammatory, catabolic, metabolic and immune-suppressive features, and a failure to return to homeostasis, which often results in a condition referred to as chronic critical illness and is not fundamentally different from the sustained host response aberrations that are induced by severe non-infectious injuries.

  • Sepsis is a very heterogeneous syndrome, and current knowledge does not enable the stratification of patients into more homogeneous subgroups in which specific and potentially targetable host response derailments drive pathology.

  • Key pro-inflammatory responses during sepsis include the activation of the complement system, the coagulation system, the vascular endothelium, neutrophils and platelets, whereas immune suppression is primarily caused by the reprogramming of antigen-presenting cells, and the apoptosis and exhaustion of lymphocytes.

  • Individuals who survive sepsis frequently suffer from long-term cognitive and physical impairments, the aetiology of which is uncertain.

  • Strategies to modulate the aberrant host response have been unsuccessful in a large number of clinical trials, which may at least in part be related to the inadequate selection of therapeutic targets and an inability to select the patients who might benefit from a certain intervention.

  • Future research should focus the discovery and validation of biomarkers that reflect the predominant pathophysiological mechanisms at different body sites, and that can guide the selection of patients for targeted therapies and the monitoring thereof.

Abstract

Sepsis is defined as a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. In sepsis, the immune response that is initiated by an invading pathogen fails to return to homeostasis, thus culminating in a pathological syndrome that is characterized by sustained excessive inflammation and immune suppression. Our understanding of the key mechanisms involved in the pathogenesis of sepsis has increased tremendously, yet this still needs to be translated into novel targeted therapeutic strategies. Pivotal for the clinical development of new sepsis therapies is the selection of patients on the basis of biomarkers and/or functional defects that provide specific insights into the expression or activity of the therapeutic target.

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Figure 1: The host response to infection and during sepsis.
Figure 2: Activation of the coagulation and complement systems during sepsis.
Figure 3: Metabolic and epigenetic pathways lead to an imbalance of immune responses in sepsis.
Figure 4: Genomic responses of leukocytes in sepsis.
Figure 5: The development of therapeutic drugs for sepsis.

References

  1. Funk, D. J., Parrillo, J. E. & Kumar, A. Sepsis and septic shock: a history. Crit. Care Clin. 25, 83–101 (2009).

    Article  PubMed  Google Scholar 

  2. Bone, R. C., Sibbald, W. J. & Sprung, C. L. The ACCP–SCCM Consensus Conference on sepsis and organ failure. Chest 101, 1481–1483 (1992).

    Article  CAS  PubMed  Google Scholar 

  3. Singer, M. et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315, 801–810 (2016). This article describes the most recent consensus definition of sepsis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Marshall, J. C. Why have clinical trials in sepsis failed? Trends Mol. Med. 20, 195–203 (2014).

    Article  PubMed  Google Scholar 

  5. Cohen, J. et al. Sepsis: a roadmap for future research. Lancet Infect. Dis. 15, 581–614 (2015).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Chan, J. K. et al. Alarmins: awaiting a clinical response. J. Clin. Invest. 122, 2711–2719 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Deutschman, C. S. & Tracey, K. J. Sepsis: current dogma and new perspectives. Immunity 40, 463–475 (2014).

    Article  CAS  PubMed  Google Scholar 

  9. Gentile, L. F. et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J. Trauma Acute Care Surg. 72, 1491–1501 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wiersinga, W. J., Leopold, S. J., Cranendonk, D. R. & van der Poll, T. Host innate immune responses to sepsis. Virulence 5, 36–44 (2014).

    Article  PubMed  Google Scholar 

  11. Merle, N. S., Noe, R., Halbwachs-Mecarelli, L., Fremeaux-Bacchi, V. & Roumenina, L. T. Complement system part II: role in immunity. Front. Immunol. 6, 257 (2015).

    PubMed  PubMed Central  Google Scholar 

  12. Guo, R. F. & Ward, P. A. Role of C5a in inflammatory responses. Annu. Rev. Immunol. 23, 821–852 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Silasi-Mansat, R. et al. Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis. Blood 116, 1002–1010 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shao, Z., Nishimura, T., Leung, L. L. & Morser, J. Carboxypeptidase B2 deficiency reveals opposite effects of complement C3a and C5a in a murine polymicrobial sepsis model. J. Thromb. Haemost. 13, 1090–1102 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Engelmann, B. & Massberg, S. Thrombosis as an intravascular effector of innate immunity. Nat. Rev. Immunol. 13, 34–45 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Levi, M. & van der Poll, T. Coagulation and sepsis. Thromb. Res. 149, 38–44 (2016).

    Article  CAS  PubMed  Google Scholar 

  17. Nieman, M. T. Protease-activated receptors in hemostasis. Blood 128, 169–177 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Danese, S., Vetrano, S., Zhang, L., Poplis, V. A. & Castellino, F. J. The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications. Blood 115, 1121–1130 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kerschen, E. J. et al. Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C. J. Exp. Med. 204, 2439–2448 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Warren, B. L. et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 286, 1869–1878 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Abraham, E. et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 290, 238–247 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. 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 

  23. Ranieri, V. M. et al. Drotrecogin alfa (activated) in adults with septic shock. N. Engl. J. Med. 366, 2055–2064 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Sorensen, O. E. & Borregaard, N. Neutrophil extracellular traps — the dark side of neutrophils. J. Clin. Invest. 126, 1612–1620 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Yipp, B. G. & Kubes, P. NETosis: how vital is it? Blood 122, 2784–2794 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Czaikoski, P. G. et al. Neutrophil extracellular traps induce organ damage during experimental and clinical sepsis. PLoS ONE 11, e0148142 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. von Bruhl, M. L. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J. Exp. Med. 209, 819–835 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Opal, S. M. & van der Poll, T. Endothelial barrier dysfunction in septic shock. J. Intern. Med. 277, 277–293 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Darwish, I. & Liles, W. C. Emerging therapeutic strategies to prevent infection-related microvascular endothelial activation and dysfunction. Virulence 4, 572–582 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Tressel, S. L. et al. A matrix metalloprotease–PAR1 system regulates vascular integrity, systemic inflammation and death in sepsis. EMBO Mol. Med. 3, 370–384 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sanchez, T. Sphingosine-1-phosphate signaling in endothelial disorders. Curr. Atheroscler. Rep. 18, 31 (2016).

    Article  CAS  PubMed  Google Scholar 

  32. Mikacenic, C. et al. Biomarkers of endothelial activation are associated with poor outcome in critical illness. PLoS ONE 10, e0141251 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Claushuis, T. A. et al. Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients. Blood 127, 3062–3072 (2016).

    Article  CAS  PubMed  Google Scholar 

  34. Wong, C. H., Jenne, C. N., Petri, B., Chrobok, N. L. & Kubes, P. Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance. Nat. Immunol. 14, 785–792 (2013). This paper demonstrates the tight interaction between haemostasis and innate immunity by showing that platelets and Kupffer cells act together in a mechanism that rapidly clears Gram-positive blood-borne bacteria.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. de Stoppelaar, S. F. et al. Thrombocytopenia impairs host defense in gram-negative pneumonia-derived sepsis in mice. Blood 124, 3781–3790 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. de Stoppelaar, S. F., van 't Veer, C. & van der Poll, T. The role of platelets in sepsis. Thromb. Haemost. 112, 666–677 (2014).

    Article  PubMed  Google Scholar 

  37. Kelly-Scumpia, K. M. et al. B cells enhance early innate immune responses during bacterial sepsis. J. Exp. Med. 208, 1673–1682 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rauch, P. J. et al. Innate response activator B cells protect against microbial sepsis. Science 335, 597–601 (2012). This paper describes innate response activator B cells as key components of the innate immune response that facilitates bacterial clearance during sepsis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Weber, G. F. et al. Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis. Science 347, 1260–1265 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hotchkiss, R. S., Monneret, G. & Payen, D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat. Rev. Immunol. 13, 862–874 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Boomer, J. S. et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 306, 2594–2605 (2011). This article reports that patients who die in the ICU following sepsis, when compared with patients who die of non-sepsis aetiologies, have biochemical, flow cytometric and immunohistochemical findings that are consistent with immunosuppression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Huang, X. et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc. Natl Acad. Sci. USA 106, 6303–6308 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Shao, R. et al. Monocyte programmed death ligand-1 expression after 3–4 days of sepsis is associated with risk stratification and mortality in septic patients: a prospective cohort study. Crit. Care 20, 124 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Venet, F. et al. Human CD4+CD25+ regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. J. Immunol. 177, 6540–6547 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Scumpia, P. O. et al. Treatment with GITR agonistic antibody corrects adaptive immune dysfunction in sepsis. Blood 110, 3673–3681 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pastille, E. et al. Modulation of dendritic cell differentiation in the bone marrow mediates sustained immunosuppression after polymicrobial sepsis. J. Immunol. 186, 977–986 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Hotchkiss, R. S. et al. Depletion of dendritic cells, but not macrophages, in patients with sepsis. J. Immunol. 168, 2493–2500 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Scumpia, P. O. et al. CD11c+ dendritic cells are required for survival in murine polymicrobial sepsis. J. Immunol. 175, 3282–3286 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Carson, W. F., Cavassani, K. A., Dou, Y. & Kunkel, S. L. Epigenetic regulation of immune cell functions during post-septic immunosuppression. Epigenetics 6, 273–283 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Filipowicz, W., Bhattacharyya, S. N. & Sonenberg, N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat. Rev. Genet. 9, 102–114 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Chan, C., Li, L., McCall, C. E. & Yoza, B. K. Endotoxin tolerance disrupts chromatin remodeling and NF-κB transactivation at the IL-1β promoter. J. Immunol. 175, 461–468 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. El Gazzar, M. et al. Chromatin-specific remodeling by HMGB1 and linker histone H1 silences proinflammatory genes during endotoxin tolerance. Mol. Cell. Biol. 29, 1959–1971 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. De Santa, F. et al. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130, 1083–1094 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. De Santa, F. et al. Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. EMBO J. 28, 3341–3352 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Liu, T. F., Yoza, B. K., El Gazzar, M., Vachharajani, V. T. & McCall, C. E. NAD+-dependent SIRT1 deacetylase participates in epigenetic reprogramming during endotoxin tolerance. J. Biol. Chem. 286, 9856–9864 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Netea, M. G., Quintin, J. & van der Meer, J. W. Trained immunity: a memory for innate host defense. Cell Host Microbe 9, 355–361 (2011). This paper introduces the term trained immunity to describe the phenomenon that mammalian innate immunity exhibits an immunological memory of past insults.

    Article  CAS  PubMed  Google Scholar 

  58. Blok, B. A., Arts, R. J., van Crevel, R., Benn, C. S. & Netea, M. G. Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines. J. Leukoc. Biol. 98, 347–356 (2015).

    Article  CAS  PubMed  Google Scholar 

  59. Quintin, J. et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12, 223–232 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. Saeed, S. et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cheng, S. C. et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Arts, R. J. et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. 24, 807–819 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yoshida, K. et al. The transcription factor ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory. Nat. Immunol. 16, 1034–1043 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. Novakovic, B. et al. β-Glucan reverses the epigenetic state of LPS-induced immunological tolerance. Cell 167, 1354–1368 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Andersson, U. & Tracey, K. J. Reflex principles of immunological homeostasis. Annu. Rev. Immunol. 30, 313–335 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Koopman, F. A. et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 113, 8284–8289 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. O'Neill, L. A., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Mills, E. L. et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167, 457–470 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Liu, T. F., Vachharajani, V. T., Yoza, B. K. & McCall, C. E. NAD+-dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response. J. Biol. Chem. 287, 25758–25769 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lachmandas, E. et al. Microbial stimulation of different Toll-like receptor signalling pathways induces diverse metabolic programmes in human monocytes. Nat. Microbiol. 2, 16246 (2016).

    Article  CAS  PubMed  Google Scholar 

  72. Cheng, S. C. et al. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat. Immunol. 17, 406–413 (2016). This paper shows that leukocytes from patients with sepsis who have immunoparalysis demonstrate a generalized metabolic defect at the level of both glycolysis and oxidative metabolism.

    Article  CAS  PubMed  Google Scholar 

  73. Dickson, R. P. The microbiome and critical illness. Lancet Respir. Med. 4, 59–72 (2016).

    Article  PubMed  Google Scholar 

  74. Prescott, H. C., Dickson, R. P., Rogers, M. A., Langa, K. M. & Iwashyna, T. J. Hospitalization type and subsequent severe sepsis. Am. J. Respir. Crit. Care Med. 192, 581–588 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Schirmer, M. et al. Linking the human gut microbiome to inflammatory cytokine production capacity. Cell 167, 1125–1136 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Clarke, T. B. et al. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat. Med. 16, 228–231 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Gauguet, S. et al. Intestinal microbiota of mice influences resistance to Staphylococcus aureus pneumonia. Infect. Immun. 83, 4003–4014 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Schuijt, T. J. et al. The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia. Gut 65, 575–583 (2016).

    Article  CAS  PubMed  Google Scholar 

  79. Karmarkar, D. & Rock, K. L. Microbiota signalling through MyD88 is necessary for a systemic neutrophilic inflammatory response. Immunology 140, 483–492 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Bo, L. et al. Probiotics for preventing ventilator-associated pneumonia. Cochrane Database Syst. Rev. 25, CD009066 (2014).

    Google Scholar 

  81. Besselink, M. G. et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 371, 651–659 (2008).

    Article  PubMed  Google Scholar 

  82. Han, S., Shannahan, S. & Pellish, R. Fecal microbiota transplant: treatment options for Clostridium difficile infection in the intensive care unit. J. Intensive Care Med. 31, 577–586 (2016).

    Article  PubMed  Google Scholar 

  83. Li, Q. et al. Successful treatment of severe sepsis and diarrhea after vagotomy utilizing fecal microbiota transplantation: a case report. Crit. Care 19, 37 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Sweeney, T. E. & Wong, H. R. Risk stratification and prognosis in sepsis: what have we learned from microarrays? Clin. Chest Med. 37, 209–218 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Scicluna, B. P. et al. A molecular biomarker to diagnose community-acquired pneumonia on intensive care unit admission. Am. J. Respir. Crit. Care Med. 192, 826–835 (2015).

    Article  CAS  PubMed  Google Scholar 

  86. van Vught, L. A. et al. Incidence, risk factors, and attributable mortality of secondary infections in the intensive care unit after admission for sepsis. JAMA 315, 1469–1479 (2016). This is a large observational study showing that ICU-acquired infections only modestly contribute to mortality in patients admitted with sepsis.

    Article  CAS  PubMed  Google Scholar 

  87. van Vught, L. A. et al. Comparative analysis of the host response to community-acquired and hospital-acquired pneumonia in critically ill patients. Am. J. Respir. Crit. Care Med. 194, 1366–1374 (2016).

    Article  CAS  PubMed  Google Scholar 

  88. Burnham, K. L. et al. Shared and distinct aspects of the sepsis transcriptomic response to fecal peritonitis and pneumonia. Am. J. Respir. Crit. Care Med. http://dx.doi.org/10.1164/rccm.201608-1685OC (2016).

  89. Xiao, W. et al. A genomic storm in critically injured humans. J. Exp. Med. 208, 2581–2590 (2011). This study demonstrates that in patients with severe blunt trauma, the early leukocyte genomic response is characterized by an increase in the expression of genes involved in systemic inflammatory and innate immune responses, and concomitant suppression of genes involved in adaptive immunity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Davenport, E. E. et al. Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir. Med. 4, 259–271 (2016). This study carried out in patients with severe community-acquired pneumonia reveals two distinct sepsis response signatures that are based on analyses of the blood leukocyte transcriptome; one of the signatures identifies individuals with an immunosuppressed phenotype.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Shalova, I. N. et al. Human monocytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1α. Immunity 42, 484–498 (2015).

    Article  CAS  PubMed  Google Scholar 

  92. Opal, S. M., Dellinger, R. P., Vincent, J. L., Masur, H. & Angus, D. C. The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C? Crit. Care Med. 42, 1714–1721 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Leentjens, J., Kox, M., van der Hoeven, J. G., Netea, M. G. & Pickkers, P. Immunotherapy for the adjunctive treatment of sepsis: from immunosuppression to immunostimulation. Time for a paradigm change? Am. J. Respir. Crit. Care Med. 187, 1287–1293 (2013).

    Article  CAS  PubMed  Google Scholar 

  94. Patil, N. K., Bohannon, J. K. & Sherwood, E. R. Immunotherapy: a promising approach to reverse sepsis-induced immunosuppression. Pharmacol. Res. 111, 688–702 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. van Vught, L. A. et al. The host response in sepsis patients developing intensive care unit-acquired secondary infections. Am. J. Respir. Crit. Care Med. http://dx.doi.org/10.1164/rccm.201606-1225OC (2017).

  96. Cruz, D. N. et al. Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA 301, 2445–2452 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Payen, D. M. et al. Early use of polymyxin B hemoperfusion in patients with septic shock due to peritonitis: a multicenter randomized control trial. Intensive Care Med. 41, 975–984 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01046669 (2016).

  99. Mass Device. Spectral Medical's Toraymyxin fails pivotal trial. MassDevice http://www.massdevice.com/spectral-medicals-toraymyxin-fails-pivotal-trial/ (2016).

  100. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02288975 (2017).

  101. Kang, J. H. et al. An extracorporeal blood-cleansing device for sepsis therapy. Nat. Med. 20, 1211–1216 (2014).

    Article  CAS  PubMed  Google Scholar 

  102. Arad, G. et al. Binding of superantigen toxins into the CD28 homodimer interface is essential for induction of cytokine genes that mediate lethal shock. PLoS Biol. 9, e1001149 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ramachandran, G. et al. CD28 homodimer interface mimetic peptide acts as a preventive and therapeutic agent in models of severe bacterial sepsis and gram-negative bacterial peritonitis. J. Infect. Dis. 211, 995–1003 (2015).

    Article  CAS  PubMed  Google Scholar 

  104. Bulger, E. M. et al. A novel drug for treatment of necrotizing soft-tissue infections: a randomized clinical trial. JAMA Surg. 149, 528–536 (2014).

    Article  CAS  PubMed  Google Scholar 

  105. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02469857 (2017).

  106. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02246595 (2016).

  107. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01598831 (2017).

  108. Leentjens, J. et al. Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am. J. Respir. Crit. Care Med. 186, 838–845 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  110. Delsing, C. E. et al. Interferon-γ as adjunctive immunotherapy for invasive fungal infections: a case series. BMC Infect. Dis. 14, 166 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Nalos, M. et al. Immune effects of interferon γ in persistent staphylococcal sepsis. Am. J. Respir. Crit. Care Med. 185, 110–112 (2012).

    Article  PubMed  Google Scholar 

  112. Rochman, Y., Spolski, R. & Leonard, W. J. New insights into the regulation of T cells by γc family cytokines. Nat. Rev. Immunol. 9, 480–490 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Unsinger, J. et al. IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J. Immunol. 184, 3768–3779 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Kasten, K. R. et al. Interleukin-7 (IL-7) treatment accelerates neutrophil recruitment through γδ T-cell IL-17 production in a murine model of sepsis. Infect. Immun. 78, 4714–4722 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Venet, F. et al. IL-7 restores lymphocyte functions in septic patients. J. Immunol. 189, 5073–5081 (2012).

    Article  CAS  PubMed  Google Scholar 

  116. Mackall, C. L., Fry, T. J. & Gress, R. E. Harnessing the biology of IL-7 for therapeutic application. Nat. Rev. Immunol. 11, 330–342 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02640807 (2016).

  118. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02797431 (2017).

  119. Inoue, S. et al. IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis. J. Immunol. 184, 1401–1409 (2010).

    Article  CAS  PubMed  Google Scholar 

  120. Conlon, K. C. et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J. Clin. Oncol. 33, 74–82 (2015).

    Article  CAS  PubMed  Google Scholar 

  121. Meisel, C. et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am. J. Respir. Crit. Care Med. 180, 640–648 (2009).

    Article  CAS  PubMed  Google Scholar 

  122. Hall, M. W. et al. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med. 37, 525–532 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02361528 (2016).

  124. Bo, L., Wang, F., Zhu, J., Li, J. & Deng, X. Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis. Crit. Care 15, R58 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Pardoll, D. M. Immunology beats cancer: a blueprint for successful translation. Nat. Immunol. 13, 1129–1132 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02576457 (2017).

  127. Shubin, N. J. et al. BTLA expression contributes to septic morbidity and mortality by inducing innate inflammatory cell dysfunction. J. Leukoc. Biol. 92, 593–603 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Inoue, S. et al. Dose-dependent effect of anti-CTLA-4 on survival in sepsis. Shock 36, 38–44 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Tuthill, C., Rios, I. & McBeath, R. Thymosin α 1: past clinical experience and future promise. Ann. NY Acad. Sci. 1194, 130–135 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Wu, J. et al. The efficacy of thymosin α 1 for severe sepsis (ETASS): a multicenter, single-blind, randomized and controlled trial. Crit. Care 17, R8 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Feng, Z., Shi, Q., Fan, Y., Wang, Q. & Yin, W. Ulinastatin and/or thymosin α1 for severe sepsis: a systematic review and meta-analysis. J. Trauma Acute Care Surg. 80, 335–340 (2016).

    Article  PubMed  Google Scholar 

  132. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02867267 (2016).

  133. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02647554 (2016).

  134. Walter, J., Ware, L. B. & Matthay, M. A. Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis. Lancet. Respir. Med. 2, 1016–1026 (2014).

    Article  CAS  PubMed  Google Scholar 

  135. Kingsley, S. M. & Bhat, B. V. Could stem cells be the future therapy for sepsis? Blood Rev. 30, 439–452 (2016).

    Article  PubMed  Google Scholar 

  136. Nemeth, K. et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E2-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat. Med. 15, 42–49 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Monsel, A. et al. Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice. Am. J. Respir. Crit. Care Med. 192, 324–336 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02883803 (2016).

  139. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02421484 (2017).

  140. Larsen, R. et al. A central role for free heme in the pathogenesis of severe sepsis. Sci. Transl Med. 2, 51ra71 (2010).

    Article  CAS  PubMed  Google Scholar 

  141. Martins, R. et al. Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nat. Immunol. 17, 1361–1372 (2016).

    Article  CAS  PubMed  Google Scholar 

  142. Vachharajani, V. T. et al. SIRT1 inhibition during the hypoinflammatory phenotype of sepsis enhances immunity and improves outcome. J. Leukoc. Biol. 96, 785–796 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Wang, X. et al. Sirtuin-2 regulates sepsis inflammation in ob/ob mice. PLoS ONE 11, e0160431 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Pierrakos, C. & Vincent, J. L. Sepsis biomarkers: a review. Crit. Care 14, R15 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Levy, M. M. et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit. Care Med. 31, 1250–1256 (2003).

    Article  PubMed  Google Scholar 

  146. Vincent, J. L. et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 22, 707–710 (1996).

    Article  CAS  PubMed  Google Scholar 

  147. Gaieski, D. F., Edwards, J. M., Kallan, M. J. & Carr, B. G. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit. Care Med. 41, 1167–1174 (2013).

    Article  PubMed  Google Scholar 

  148. Fleischmann, C. et al. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am. J. Respir. Crit. Care Med. 193, 259–272 (2016).

    Article  CAS  PubMed  Google Scholar 

  149. Kaukonen, K. M., Bailey, M., Suzuki, S., Pilcher, D. & Bellomo, R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012. JAMA 311, 1308–1316 (2014). This large observational study in Australia and New Zealand finds that absolute mortality in severe sepsis decreased from 35.0% to 18.4% between 2000 and 2012, which represents an annual rate of absolute decrease of 1.3%.

    Article  CAS  PubMed  Google Scholar 

  150. Rhodes, A. et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2016. Crit. Care Med. 45, 486–552 (2017). This is the most recent version of the consensus guidelines for the management of sepsis and septic shock.

    Article  PubMed  Google Scholar 

  151. Iwashyna, T. J., Ely, E. W., Smith, D. M. & Langa, K. M. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 304, 1787–1794 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Prescott, H. C., Osterholzer, J. J., Langa, K. M., Angus, D. C. & Iwashyna, T. J. Late mortality after sepsis: propensity matched cohort study. BMJ 353, i2375 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Yende, S. et al. Long-term quality of life among survivors of severe sepsis: analyses of two international trials. Crit. Care Med. 44, 1461–1467 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by a TOP subsidy from the Netherlands Organization for Scientific Research (to T.v.d.P. and M.G.N.). M.G.N. was partly supported by a European Research Council Consolidator Grant (3310372) and a Spinoza grant from the Netherlands Organization for Scientific Research.

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Glossary

Homeostasis

A process by which biological systems maintain stability while adjusting to circumstances, which promotes survival.

Pathogen-associated molecular patterns

(PAMPs). Molecular motifs that are associated with classes of pathogens and are capable of ligating innate immune receptors known as pattern recognition receptors.

Pattern recognition receptors

(PRRs). Receptors that recognize molecules expressed by pathogens and host molecules released by injured cells: that is, pathogen-associated molecular patterns and damage-associated molecular patterns, respectively.

Damage-associated molecular patterns

(DAMPs). Host-derived molecules — such as uric acid, ATP and heat shock proteins — that are released from injured cells and can activate pattern recognition receptors.

Immunothrombosis

Thrombosis that is initiated by the innate immune system and that aims to provide a first line of defence to locally control an infection.

Protease-activated receptors

(PARs). A family of G protein-coupled receptors that can be specifically activated by coagulation proteases and various other serine proteases.

Histones

Intranuclear proteins that package and order the DNA into structural units called nucleosomes.

Glycocalyx

A complex network of cell-bound proteoglycans, glycosaminoglycan side chains and sialoproteins that lines the luminal side of endothelial cells.

Lymphocyte exhaustion

A term that is used to indicate the functional impairment of antigen-specific lymphocytes in the context of a persistently high antigen load.

Apoptosis

A common form of cell death that is also known as intrinsic or programmed cell death. Many physiological and developmental stimuli cause apoptosis, and this mechanism is frequently used to delete unwanted, superfluous or potentially harmful cells, such as those undergoing transformation.

Epigenetic regulation

Reversible biochemical changes to chromatin that influence gene expression but do not involve alterations in DNA sequence.

MicroRNAs

(miRNAs). Small single-stranded RNA molecules that function in the post-transcriptional regulation of gene expression.

Demethylase

An enzyme that induces demethylation: that is, the removal of a methyl group from a molecule.

Deacetylase

An enzyme that induces deacetylation: that is, the removal of an acetyl group from a molecule.

Trained immunity

Memory of the innate immune system that is mediated by monocytes, macrophages and natural killer cells, and manifests as protection against reinfection by the same or different pathogens in organisms that lack adaptive immune responses.

Warburg effect

The phenomenon in which inflammatory and cancer cells demonstrate a shift in energy metabolism away from oxidative phosphorylation (which is dominant in resting cells) towards aerobic glycolysis, thereby making them able to more rapidly provide ATP and metabolic intermediates for the biosynthesis of immune and inflammatory proteins.

Mesenchymal stem cells

Multipotent cells that can be derived from a wide variety of tissues including bone marrow, adipose tissue, cord blood and muscles. The immuno- phenotype of these cells typically includes the expression of surface markers such as CD73, CD90 and CD105, and a lack of the haematopoietic markers CD45, CD34, CD14 and CD11.

Theranostics

Diagnostic testing used in combination with targeted therapeutics.

Superantigens

Antigens that induce nonspecific activation of T cells, which results in polyclonal T cell activation.

Immune checkpoints

Negative regulators of the immune system that are important for maintaining self-tolerance, preventing autoimmunity and protecting tissues from immune-mediated injury.

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van der Poll, T., van de Veerdonk, F., Scicluna, B. et al. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol 17, 407–420 (2017). https://doi.org/10.1038/nri.2017.36

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