Sepsis pp 89-104 | Cite as

Molecular Targets for Therapy

  • Andre C. KalilEmail author
  • Steven M. Opal
Part of the Respiratory Medicine book series (RM)


Defining potential molecular targets for sepsis therapeutics has proven to be a real challenge in translating laboratory findings into effective clinical treatments. A myriad of possible targets have been proposed from preclinical studies but they often have overlapping pathologic functions, can differ depending upon the causative microbial pathogen, site of infection, and status of the immune response of the host at the time of treatment is initiated. When attempting to modulate the host response in critically ill patients during an ongoing systemic infection, the capacity to do harm is substantial and the net effects of such interventions on host defenses and antimicrobial clearance mechanisms in individual patients are highly variable. Finding a final common pathway that drives sepsis pathophysiology has been elusive and has limited progress in developing new sepsis therapeutics. Current aims to improve outcomes in sepsis are now focused upon regulation of the coagulation system; maintenance and repair of endothelial surfaces and the blood compartment; epithelial membrane integrity; regulating the dysfunctional systemic immune response in sepsis; and bolstering host defenses against microbial toxins and virulence.


Sepsis Septic shock Molecular targets for sepsis Sepsis therapies Apoptosis Endothelial barrier Sepsis-induced immune suppression 


  1. 1.
    Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. Crit Care Med. 2009;37(1):291–304. PubMed PMID: 19050640CrossRefPubMedGoogle Scholar
  2. 2.
    van der Poll T, Opal SM. Host-pathogen interactions in sepsis. Lancet Infect Dis. 2008;8(1):32–43. PubMed PMID: 18063412CrossRefPubMedGoogle Scholar
  3. 3.
    Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA. 2001;286(15):1869–78. PubMed PMID: 11597289CrossRefPubMedGoogle Scholar
  4. 4.
    Afshari A, Wetterslev J, Brok J, Moller AM. Antithrombin III for critically ill patients. Cochrane Database Syst Rev. 2008;3:CD005370.PubMed PMID: 18646125Google Scholar
  5. 5.
    Afshari A, Wetterslev J, Brok J, Moller A. Antithrombin III in critically ill patients: systematic review with meta-analysis and trial sequential analysis. BMJ. 2007;335(7632):1248–51. PubMed Central PMCID: 2137061CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Wiedermann CJ, Kaneider NC. A systematic review of antithrombin concentrate use in patients with disseminated intravascular coagulation of severe sepsis. Blood Coagul Fibrinolysis. 2006;17(7):521–6. PubMed PMID: 16988545CrossRefPubMedGoogle Scholar
  7. 7.
    Chu AJ. Tissue factor, blood coagulation, and beyond: an overview. Int J Inflamm. 2011;2011:367284. PubMed Central PMCID: 3176495CrossRefGoogle Scholar
  8. 8.
    Abraham E, Reinhart K, Svoboda P, Seibert A, Olthoff D, Dal Nogare A, et al. Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study. Crit Care Med. 2001;29(11):2081–9. PubMed PMID: 11700399CrossRefPubMedGoogle Scholar
  9. 9.
    Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL, et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA. 2003;290(2):238–47. PubMed PMID: 12851279CrossRefPubMedGoogle Scholar
  10. 10.
    Taylor Jr FB, Chang A, Esmon CT, D'Angelo A, Vigano-D'Angelo S, Blick KE. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest. 1987;79(3):918–25. PubMed Central PMCID: 424237CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Li W, Zheng X, Gu J, Hunter J, Ferrell GL, Lupu F, et al. Overexpressing endothelial cell protein C receptor alters the hemostatic balance and protects mice from endotoxin. J Thromb Haemost. 2005;3(7):1351–9. PubMed PMID: 15978090CrossRefPubMedGoogle Scholar
  12. 12.
    Murakami K, Okajima K, Uchiba M, Johno M, Nakagaki T, Okabe H, et al. Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats. Blood. 1996;87(2):642–7. PubMed PMID: 8555486PubMedGoogle Scholar
  13. 13.
    Marti-Carvajal AJ, Sola I, Lathyris D, Cardona AF. Human recombinant activated protein C for severe sepsis. Cochrane Database Syst Rev. 2012;3:CD004388.PubMed PMID: 22419295Google Scholar
  14. 14.
    Kalil AC, LaRosa SP. Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression. Lancet Infect Dis. 2012;12(9):678–86. PubMed PMID: 22809883CrossRefPubMedGoogle Scholar
  15. 15.
    Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699–709. PubMed PMID: 11236773CrossRefPubMedGoogle Scholar
  16. 16.
    Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366(22):2055–64. PubMed PMID: 22616830CrossRefPubMedGoogle Scholar
  17. 17.
    Kalil AC, Florescu DF. Severe sepsis: are PROWESS and PROWESS-SHOCK trials comparable? A clinical and statistical heterogeneity analysis. Crit Care. 2013;17(4):167. PubMed Central PMCID: 3706817CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R, 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(1):31–41. PubMed PMID: 17059423CrossRefPubMedGoogle Scholar
  19. 19.
    Vincent JL, Ramesh MK, Ernest D, LaRosa SP, Pachl J, Aikawa N, et al. A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation. Crit Care Med. 2013;41(9):2069–79. PubMed PMID: 23979365CrossRefPubMedGoogle Scholar
  20. 20.
    Jaimes F, De La Rosa G, Morales C, Fortich F, Arango C, Aguirre D, et al. Unfractioned heparin for treatment of sepsis: a randomized clinical trial (The HETRASE Study). Crit Care Med. 2009;37(4):1185–96. PubMed PMID: 19242322CrossRefPubMedGoogle Scholar
  21. 21.
    Levi M, Levy M, Williams MD, Douglas I, Artigas A, Antonelli M, et al. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med. 2007;176(5):483–90. PubMed PMID: 17556722CrossRefPubMedGoogle Scholar
  22. 22.
    Zarychanski R, Abou-Setta AM, Kanji S, Turgeon AF, Kumar A, Houston DS, et al. The efficacy and safety of heparin in patients with sepsis: a systematic review and metaanalysis. Crit Care Med. 2014; Dec 9. PubMed PMID: 25493972Google Scholar
  23. 23.
    Wildhagen K, García de Frutos P, Reutelingsperger C, Schrijver R, Areste C. Ortega-Gomez et al. Nonanticoagulant heparin prevents histone-mediated cytotoxicity in vitro and improves survival in sepsis. Blood. 2014;123(7):1098–101. PubMed PMID: 24264231.CrossRefPubMedGoogle Scholar
  24. 24.
    Brinkman V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–5. Pub Med PMID: 15001782.CrossRefGoogle Scholar
  25. 25.
    Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med. 2007;13(4):463–9. Pub Med PMID: 17384648.CrossRefPubMedGoogle Scholar
  26. 26.
    Xu J, Zhang X, Pelayo R, Monestier M, Ammollo CT, Semeraro F, et al. Extracellular histones are major mediators of death in sepsis. Nat Med. 2009;15(11):1318–21. Pub Med PMID: 19855397.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Saffarzadeh M, Juenemann C, Queisser MA, Lochnit G, Barreto G, Galuska SP, et al. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones. PLoS One. 2012;7(2):e32366. PubMed PMID: 22389696.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood. 2003;101(10):3765–77. PubMed PMID: 12543869CrossRefPubMedGoogle Scholar
  29. 29.
    Schouten M, Wiersinga WJ, Levi M, van der Poll T. Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol. 2008;83(3):536–45. PubMed PMID: 19751574CrossRefPubMedGoogle Scholar
  30. 30.
    Levi M, van der Poll T. Endothelial injury in sepsis. Intensive Care Med. 2013;39(10):1839–42. PubMed PMID: 23925547CrossRefPubMedGoogle Scholar
  31. 31.
    Bockmeyer CL, Claus RA, Budde U, Kentouche K, Schneppenheim R, Losche W, et al. Inflammation-associated ADAMTS13 deficiency promotes formation of ultra-large von Willebrand factor. Haematologica. 2008;93(1):137–40. PubMed PMID: 18166799CrossRefPubMedGoogle Scholar
  32. 32.
    de Stoppelaar SF, van 't Veer C, van der Poll T. The role of platelets in sepsis. Thromb Haemost. 2014;112(4):666–77. PubMed PMID: 24966015CrossRefPubMedGoogle Scholar
  33. 33.
    Opal SM, van der Poll T. Endothelial barrier dysfunction in septic shock. J Intern Med. 2015;277(3):277–93. doi: 10.1111/joim.12331. PubMed PMID: 25418337CrossRefPubMedGoogle Scholar
  34. 34.
    Sevigny LM, Zhang P, Bohm A, Lazarides K, Perides G, Covic L, et al. Interdicting protease-activated receptor-2-driven inflammation with cell-penetrating pepducins. Proc Natl Acad Sci U S A. 2011;108(20):8491–6. PubMed PMID: 21536878CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Covic L, Gresser AL, Talavera J, Swift S, Kuliopulos A. Activation and inhibition of G protein-coupled receptors by cell-penetrating membrane-tethered peptides. Proc Natl Acad Sci U S A. 2002;99(2):643–8. PubMed PMID: 11805322CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Kaneider NC, Leger AJ, Agarwal A, Nguyen N, Perides G, Derian C, et al. ‘Role reversal’ for the receptor PAR1 in sepsis-induced vascular damage. Nat Immunol. 2007;8(12):1303–12. PubMed PMID: 179657:1303–12.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Lee WL, Slutsky AS. Sepsis and endothelial permeability. N Engl J Med. 2010;363(7):689–91. PubMed PMID: 20818861CrossRefPubMedGoogle Scholar
  38. 38.
    London NR, Zhu W, Bozza FA, Smith MC, Greif DM, Sorensen LK, et al. Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza. Sci Transl Med. 2010;2:23ra19. PubMed PMID: 20375003CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Cohen J, Vincent J-L, Adhikari FR, Machado F, Angus D, Calandra T, et al. Sepsis: a roadmap for future research. Lancet Infect Dis. 2015;15:581–614.CrossRefPubMedGoogle Scholar
  40. 40.
    Dominguez J, Samocha A, Liang Z, Burd EM, Farris AB, Coopersmith CM. Inhibition of IKKB in enterocytes exacerbates sepsis-induced intestinal injury and worsens mortality. Crit Care Med. 2013;41:e275–85. PubMed PMID: 23939348.CrossRefPubMedGoogle Scholar
  41. 41.
    Deutchman CS, Tracey KJ. Sepsis: current dogma and new perspectives. Immunity. 2014;40:463–75. PubMed PMID: 24745331CrossRefGoogle Scholar
  42. 42.
    Human Microbiome Project C. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486(7402):207–14. PubMed PMID: 22699609CrossRefGoogle Scholar
  43. 43.
    Pearce MM, Hilt EE, Rosenfeld AB, Zilliox JM, Thomas-White K, Fok C, et al. The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. mBio. 2014;5:1–12. PubMed PMID: 25006228.CrossRefGoogle Scholar
  44. 44.
    Blaser MJ. The microbiome revolution. J Clin Invest. 2014;124(10):4162–5. PubMed PMID: 25271724CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Fink M, Warren H. Strategies to improve drug development for sepsis. Nat Rev Drug Discov. 2014;10:1–18. PubMed PMID: 25190187Google Scholar
  46. 46.
    Nair V, Soraisham A. Probiotics and prebiotics: role in prevention of nosocomial sepsis in preterm infants. Int J Pediatr. 2013;2013:1–8. Article 874726, PubMed PMID: 23401695CrossRefGoogle Scholar
  47. 47.
    Weichert S, Schroten H, Adam R. The role of prebiotics and probiotics in prevention and treatment of childhood infectious diseases. Pediatr Infect Dis J. 2012;31(8):859–62. PubMed PMID: 22801095CrossRefPubMedGoogle Scholar
  48. 48.
    Novak J, Katz J. Probiotics and prebiotics for gastrointestinal infections. Curr Infect Dis Rep. 2006;8(2):103–9. PubMed PMID: 16524546CrossRefPubMedGoogle Scholar
  49. 49.
    Strunk T, Koilmann T, Patola S. Probiotics to prevent early-life infection. Lancet Infect Dis. 2015;15:378–9. PubMed PMID: 25942569CrossRefPubMedGoogle Scholar
  50. 50.
    Besselink MG, van Santvoort HC, Renooij W, de Smet MB, Fischer K, Timmerman HM, et al. Intestinal barrier dysfunction in a randomized trial of a specific probiotic composition in acute pancreatitis. Ann Surg. 2009;250:712–9. PubMed PMID: 19801929.CrossRefPubMedGoogle Scholar
  51. 51.
    Zaborin A, Defazio J, Kade M, Deatherage Kaiser BL, Belogortseva N, Camp II DG, et al. Phosphatecontaining Polyethylene glycol polymers prevent lethal sepsis by multidrug-resistant pathogens. Antimicrob Agents Chemother. 2014;58:966–77. PubMed PMID: 24277029.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Buffie C, Bucci V, Stein R, McKenney P, Ling L, Gobourne A, et al. Precision microbiome reconstitution restores tile acid mediated resistance to Clostridium difficile. Nature. 2014. doi: 10.1038/nature13828. PubMed PMID: 25337874.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Egea L, McAllister C, Lakhdari O, Minev I, Shenouda S, Kagnoff MF, et al. GM-CSF produced by non-hematopoietic cells in required for early epithelial cell proliferation and repair of injured colonic mucosa. J Immunol. 2013;190(4):1702–13. PubMed PMID: 233258.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Liu Y. Hepatocyte growth factor promotes renal epithelial cell survival by dual mechanisms. Am J Physiol. 1999;277(4 Pt 2):F624–33. PubMed PMID: 10516287PubMedGoogle Scholar
  55. 55.
    Opal SM, Keith JC, Jhung J, Parejo N, Marchese E, Maganti V, et al. Orally administered recombinant human interleukin-11 is protective in experimental neutropenic sepsis. J Infect Dis. 2003;187:70–6. PubMed PMID: 12508148.CrossRefPubMedGoogle Scholar
  56. 56.
    Xu MJ, Feng D, Wang H, Guan Y, Yan X, Gao B, et al. IL-22 ameliorates renal ischemia-reperfusion injury by targeting proximal tubule epithelium. J Am Soc Nephrol. 2014;25:967–77. PubMed: 24459233.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Hunninghake GW, Doerschug KC, Nymon AB, Schmidt GA, Meyerholz DK, Ashare A, et al. Insulin-like growth factor-1 levels contribute to the development of bacterial translocation in sepsis. Am J Respir Crit Care Med. 2010;182:517–25. PubMed PMID: 20413631.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Kolodziej L, Lodolce J, Chang J, Schneider J, Grimm W, Bartulis S, et al. TNFAIP3 maintains intestinal barrier function and supports epithelial cell tight junctions. PLoS One. 2011;6:1–11. PubMed PMID: 22031828.CrossRefGoogle Scholar
  59. 59.
    Yang R, Harada T, Mollen KP, Prince JM, Levy RM, Englert JA, et al. Anti-HMGB1 neutralizing antibody ameliorates gut barrier dysfunction and improves survival after hemorrhagic shock. Mol Med. 2006;12:105–14. PubMed PMID: 16953558.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Qin S, Wang H, Yuan R, Li H, Ochani M, Ochani K, et al. Role of HMGV1 in apoptosis-mediated sepsis lethality. J Exp Med. 2006;203:1637–42. PubMed PMID: 16818669.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Li J, Kokkola R, Tabibzadeh S, Yang R, Ochani M, Qiang X, et al. Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Mol Med. 2003;9:37–45. PubMed PMID: 12765338.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Fiuza C, Bustin M, Talwar S, Tropea M, Gertenberger E, Shelhamer JH, et al. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood. 2003;101:2652–60. PubMed PMID: 14684474CrossRefPubMedGoogle Scholar
  63. 63.
    Wolfson RK, Chiang ET, Garcia JGN. HMGB1 induces human lung endothelial cell cytoskeletal rearrangement and barrier disruption. Microvasc Res. 2011;81(2):189–97. PubMed PMID: 21146549CrossRefPubMedGoogle Scholar
  64. 64.
    Huang W, Liu Y, Li L, Zhang R, Liu W, Wu J, et al. HMGB1 increases permeability of the endothelial cell monolayer via RAGE and Src family tyrosine kinases. Inflammation. 2012;35(1):350–62. PubMed PMID: 21494799CrossRefPubMedGoogle Scholar
  65. 65.
    Chavan SS, Huerta PT, Robbiati S, Valdes-Ferrer SI, Ochani M, Dancho M, et al. HMGB1 Mediates cognitive impairment in sepsis survivors. Mol Med. 2012;18:930–7. PubMed PMID: 22634723.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Jeong SJ, Lim BJ, Park S, Choi D, Kim HW, Ku NS, et al. The effect of sRAGE-Fc fusion protein attenuates inflammation and decreases mortality in a murine cecal ligation and puncture model. Inflamm Res. 2012;61:1211–8. PubMed PMID: 22777145.CrossRefPubMedGoogle Scholar
  67. 67.
    DiNubile M. Adjunctive treatment of severe sepsis. Lancet Infect Dis. 2013;13:917–8. PubMed PMID: 24156894CrossRefPubMedGoogle Scholar
  68. 68.
    Cruz DN, Perazella MA, Bellomo R, de Cal M, Polanco N, Corradi V, et al. Effectiveness of polymyxin B-immobilized fiber column in sepsis: a systematic review. Crit Care. 2007;11(2):R47. PubMed PMID: 17448226.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Basu R, Pathak S, Goyal J, Chaudhry R, Goel R, et al. Use of a novel hemoadsorption device for cytokine removal as adjuvant therapy in a patient with septic shock with multi-organ dysfunction: a case study. Indian J Crit Care Med. 2014;18(12):822–4. PubMed PMID: 25538418CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Honore P, Jacobs R, Joannes-Boyau O, De Regt J, De Waele E. Newly designed CRRT membranes for sepsis and SIRS—a pragmatic approach for bedside intensivists summarizing the more recent advances: a systematic structured review. ASAIO J. 2013;59(2):99–106. PubMed PMID: 23438770CrossRefPubMedGoogle Scholar
  71. 71.
    Kang JH, Super M, Yung DW, Cooper RM, Domansky K. An extracorporeal blood-cleansing device for sepsis therapy. Nat Med. 2014;20(10):1211–6. PubMed PMID: 25216635CrossRefPubMedGoogle Scholar
  72. 72.
    McCrea K, Wart R, LaRosa S. Removal of Carbapenem-Resistant Enterobacteriaceae (CRE) from blood by heparin-functional hemoperfusion media. PLoS One. 2014;9(12):e114242.Google Scholar
  73. 73.
    Delano FA, Hoyt DB, Schmid-Schonbein GW. Pancreatic digestive enzyme blockade in the intestine increases survival after experimental shock. Sci Transl Med. 2013;5:169ra11. PubMed PMID: 23345609CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet. 2002;360:219–23. PubMed PMID: 1133657CrossRefPubMedGoogle Scholar
  75. 75.
    Singer M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence. 2014;5:66–72. PubMed PMID: 24185508CrossRefPubMedGoogle Scholar
  76. 76.
    Maldonado A, Gerriets V, Rathmell J. Matched and mismatched metabolic fuels in lymphocyte function. Semin Immunol. 2012;24:405–13. PubMed PMID: 23290889CrossRefGoogle Scholar
  77. 77.
    McGettrick A, O’Neill A. How metabolism generates signals during innate immunity and inflammation. J Biol Chem. 2013;288:22893–8. PubMed PMID: 23798679CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Artenstein A, Opal SM. Proprotein convertases in health and disease. N Engl J Med. 2011;365:2507–18. PubMed PMID: 22204726CrossRefPubMedGoogle Scholar
  79. 79.
    Walley KR, Thain KR, Russell JA, Reilly MP, Meyer NJ, Ferguson JF, et al. PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci Transl Med. 2014;6:1–10. PubMed PMID: 25320235.CrossRefGoogle Scholar
  80. 80.
    Spite M, Norling LV, Summers L, Yang R, Cooper D, Petasis NA, et al. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature. 2009;461:1287–91. PubMed PMID: 19865173.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Hotchkiss R, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13:862–74. PubMed PMID: 24232462CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Hotchkiss RS, Opal SM. Immunotherapy for sepsis: a new approach against an ancient foe. N Engl J Med. 2010;363(1):87–9. PubMed PMID: 20592301CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Kalil AC, Florescu DR. Prevalence and mortality associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit. Crit Care Med. 2009;37(8):2350–8. PubMed PMID: 18531944CrossRefPubMedGoogle Scholar
  84. 84.
    Walton AH, Muenzer JT, Rasche D, Boomer JS, Sato B, Brownstein BH, et al. Reactivation of multiple viruses in patients with sepsis. PLoS One. 2014;9(6):e98819.PubMed PMID: 24919177CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    DeVlaminck I, Khush K, Strehl C, Kohli B, Luikart H, Neff NF, et al. Temporal response of the human virome to immunosuppression and antiviral therapy. Cell. 2013;155:1178–87. PubMed PMID: 24267896.CrossRefGoogle Scholar
  86. 86.
    Wu J, Zhou L, Liu J, Ma G, Kou Q, He Z, et al. The efficacy of thymosin alpha 1 for severe sepsis (ETASS): a multicenter, single-blind, randomized and controlled trial. Crit Care. 2013;17(1):R8. PubMed PMID: 23327199.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Unsinger J, Burnham CA, McDonough J, Morre M, Prakash PS, Caldwell CC, et al. Interleukin 7 ameliorates immune dysfunction and improves survival in a two hit model of fungal sepsis. J Infect Dis. 2012;206(4):606–16. PubMed PMID: 22693226.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Inoue S, Unsinger J, Davis CG, Muenzer JT, Ferguson TA, Chang K, et al. IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis. J Immunol. 2010;184:1401–9. PubMed PMID: 20026737.CrossRefPubMedGoogle Scholar
  89. 89.
    Walter J, Ware L, Matthay M. Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis. Lancet. 2014;2:1016–26. PubMed PMID: 25465643PubMedGoogle Scholar
  90. 90.
    Chahin A, Opal S, Zorzopulos J, Jobes D, Migdady Y, et al. The noval immunotherapeutic oligodeoxynucleotide IMT504 protects neutropenic animals from fatal Pseudomonas aeruginosa bacteremia and sepsis. Antimicrob Agents Chemother. 2015;59(2):1225–9. PubMed PMID: 25512413.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Elias F, Flo J, Lopez RA, Zorzopulos J, Montaner A, Rodriguez JM, et al. Strong cytosine quanosine-independent immunostimulation in humans and other primates by synthetic oligodeoxynucleotides with PyNTTTTGT motifs. J Immunol. 2003;171(7):3697–704. PubMed PMID: 14500668.CrossRefPubMedGoogle Scholar
  92. 92.
    Cavaillon J-M, Eisen D, Annane D. Is boosting the immune system in sepsis appropriate? Crit Care Med. 2014;18:216. PubMed PMID: 24886820Google Scholar
  93. 93.
    Osuuchowski M, Connett J, Welch K, Granger J, Remick D, et al. Stratification is the key: inflammatory biomarkers accurately direct immunomodulatory therapy in experimental sepsis. Crit Care Med. 2009;37:1576–72. PubMed PMID: 24238100.CrossRefGoogle Scholar
  94. 94.
    Ramachandran G, Kaempfer R, Chung CS, Shirvan A, Chahin AB, Palardy J, et al. CD 28 homodimer interface mimetic peptide as a novel inhibitor in experimental models of gram negative sepsis. J Infect Dis. 2014. PubMed PMID: 25305323.Google Scholar
  95. 95.
    Ramachandran G, Tulapurkar ME, Harris KM, Arad G, Shivran A, Shemesh R, et al. A peptide antagonist of CD 28 signaling attenuates toxic shock and necrotizing soft tissue infection induced by Streptococcus pyogenes. J Infect Dis. 2013;206(12):1869–77. PubMed PMID: 23493729CrossRefGoogle Scholar
  96. 96.
    Bulger EM, Maier RV, Sperry J, Joshi M, Henry S, Moore FA, et al. A novel drug for treatment of necrotizing soft tissue infections: results of a phase 2a randomized controlled trial of AB103, a CD28 co-stimulatory receptor modulator. JAMA Surg. 2014. doi: 10.1001/jamasurg.2013.4841. PubMed PMID:24740134.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Infectious Disease Division, Department of Internal MedicineUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Infectious Disease Division, Memorial Hospital of RIAlpert Medical School of Brown UniversityPawtucketUSA

Personalised recommendations