Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Seminars in Immunopathology
Published in: Seminars in Immunopathology 1/2008

01-02-2008 | Review

Severe sepsis and Toll-like receptors

Authors: Hongmei Gao, Susannah K. Leaver, Anne Burke-Gaffney, Simon J. Finney

Published in: Seminars in Immunopathology | Issue 1/2008

Login to get access

Abstract

Severe sepsis dominates the mortality of non-cardiac intensive care units. The ingenious Toll-like receptor (TLR) system can recognise many infectious organisms through relatively few receptors to trigger pro-inflammatory and anti-inflammatory cytokine release. Further complexity arises from positive and negative signalling feedback loops. Severe sepsis may be a consequence of an inappropriately excessive response or inadequate endogenous negative feedback. Therapies targeting these pathways are currently being evaluated. Alternatively, in clinical scenarios such as compensatory anti-inflammatory response syndrome, chronic viral sepsis or inadequate vaccine function, TLR signalling may be inadequate. TLR agonists may augment the innate response and are being investigated.
Literature
1.
Strehlow MC, Emond SD, Shapiro NI, Pelletier AJ, Camargo CA Jr (2006) National study of emergency department visits for sepsis, 1992 to 2001. Ann Emerg Med 48(3):326–331, 331 e1–3
2.
Sands KE, Bates DW, Lanken PN, Graman PS, Hibberd PL, Kahn KL, Parsonnet J, Panzer R, Orav EJ, Snydman DR, Black E, Schwartz JS, Moore R, Johnson BL Jr, Platt R (1997) Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA 278(3):234–2340PubMed
3.
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29(7):1303–1310PubMed
4.
Martin GS, Mannino DM, Eaton S, Moss M (2003) The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348(16):1546–1554PubMed
5.
Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348(2):138–150PubMed
6.
Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344(10):699–709PubMed
7.
Perl TM, Dvorak L, Hwang T, Wenzel RP (1995) Long-term survival and function after suspected gram-negative sepsis. JAMA 274(4):338–345PubMed
8.
Kaarlola A, Pettila V, Kekki P (2003) Quality of life six years after intensive care. Intensive Care Med 29(8):1294–1299PubMed
9.
Pasteur L (1879) Septicemie puerperale. Bull Acad Natl Méd (Paris) 8:271–274, 505–508
10.
Pfeiffer R (1892) Untersuchungen über das Cholera. Gift Z Hyg Infectionskr 11:393–412
11.
Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovacs JA, Wesley RA, Parrillo JE (1989) The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 321(5):280–287PubMedCrossRef
12.
Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282(5396):2085–2088PubMed
13.
Poltorak A, Smirnova I, He X, Liu MY, Van Huffel C, McNally O, Birdwell D, Alejos E, Silva M, Du X, Thompson P, Chan EK, Ledesma J, Roe B, Clifton S, Vogel SN, Beutler B (1998) Genetic and physical mapping of the Lps locus: identification of the toll-4 receptor as a candidate gene in the critical region. Blood Cells Mol Diseases 24(3):340–55
14.
Takeda K, Akira S (2005) Toll-like receptors in innate immunity. Int Immunol 17(1):1–14PubMed
15.
Dunne A, O'Neill LA (2005) Adaptor usage and Toll-like receptor signaling specificity. FEBS Lett 579(15):3330–3335PubMed
16.
Beutler B (2004) Inferences, questions and possibilities in Toll-like receptor signalling. Nature 430(6996):257–263PubMed
17.
Morath S, Geyer A, Spreitzer I, Hermann C, Hartung T (2002) Structural decomposition and heterogeneity of commercial lipoteichoic acid preparations. Infect Immun 70(2):938–944PubMed
18.
Travassos LH, Girardin SE, Philpott DJ, Blanot D, Nahori MA, Werts C, Boneca IG (2004) Toll-like receptor 2-dependent bacterial sensing does not occur via peptidoglycan recognition. EMBO Rep 5(10):1000–1006PubMed
19.
van Langevelde P, van Dissel JT, Ravensbergen E, Appelmelk BJ, Schrijver IA, Groeneveld PH (1998) Antibiotic-induced release of lipoteichoic acid and peptidoglycan from Staphylococcus aureus: quantitative measurements and biological reactivities. Antimicrob Agents Chemother 42(12):3073–3078PubMed
20.
Lee MS, Kim YJ (2007) Signaling pathways downstream of pattern-recognition receptors and their cross talk. Annu Rev Biochem 76:447–480PubMed
21.
van Aubel RA, Keestra AM, Krooshoop DJ, van Eden W, van Putten JP (2007) Ligand-induced differential cross-regulation of Toll-like receptors 2, 4 and 5 in intestinal epithelial cells. Mol Immunol 44(15):3702–3714PubMed
22.
American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. (1992) Crit Care Med 1992 20(6):864–874
23.
Sriskandan S, Cohen J (1999) Gram-positive sepsis. Mechanisms and differences from Gram-negative sepsis. Infect Dis Clin North Am 13(2):397–412PubMed
24.
Fisher CJ Jr, Opal SM, Dhainaut JF, Stephens S, Zimmerman JL, Nightingale P, Harris SJ, Schein RM, Panacek EA, Vincent JL et al (1993) Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. The CB0006 Sepsis Syndrome Study Group. Crit Care Med 21(3):318–327PubMed
25.
Fisher CJ Jr, Agosti JM, Opal SM, Lowry SF, Balk RA, Sadoff JC, Abraham E, Schein RM, Benjamin E (1996) Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med 334(26):1697–702PubMed
26.
Bjerre A, Brusletto B, Hoiby EA, Kierulf P, Brandtzaeg P (2004) Plasma interferon-gamma and interleukin-10 concentrations in systemic meningococcal disease compared with severe systemic Gram-positive septic shock. Crit Care Med 32(2):433–438PubMed
27.
Cohen J, Carlet J (1996) INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group. Crit Care Med 24(9):1431–1440PubMed
28.
Dhainaut JF, Tenaillon A, Le Tulzo Y, Schlemmer B, Solet JP, Wolff M, Holzapfel L, Zeni F, Dreyfuss D, Mira JP et al (1994) Platelet-activating factor receptor antagonist BN 52021 in the treatment of severe sepsis: a randomized, double-blind, placebo-controlled, multicenter clinical trial. BN 52021 Sepsis Study Group. Crit Care Med 22(11):1720–1728PubMedCrossRef
29.
Fein AM, Bernard GR, Criner GJ, Fletcher EC, Good JT Jr, Knaus WA, Levy H, Matuschak GM, Shanies HM, Taylor RW, Rodell TC (1997) Treatment of severe systemic inflammatory response syndrome and sepsis with a novel bradykinin antagonist, deltibant (CP-0127). Results of a randomized, double-blind, placebo-controlled trial. CP-0127 SIRS and Sepsis Study Group. JAMA 277(6):482–487PubMed
30.
Opal SM, Garber GE, LaRosa SP, Maki DG, Freebairn RC, Kinasewitz GT, Dhainaut JF, Yan SB, Williams MD, Graham DE, Nelson DR, Levy H, Bernard GR (2003) Systemic host responses in severe sepsis analyzed by causative microorganism and treatment effects of drotrecogin alfa (activated). Clin Infect Dis 37(1):50–58PubMed
31.
Peters RP, van Agtmael MA, Danner SA, Savelkoul PH, Vandenbroucke-Grauls CM (2004) New developments in the diagnosis of bloodstream infections. Lancet Infect Dis 4(12):751–760PubMed
32.
Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM (2004) Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 32(3):858–873PubMed
33.
Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB (2004) Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 39(3):309–317PubMed
34.
O’Neill LA (2003) Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases. Curr Opin Pharmacol 3(4):396–403PubMed
35.
Lien E, Ingalls RR (2002) Toll-like receptors. Crit Care Med 30(1 Suppl):S1–S11
36.
Gao JJ, Xue Q, Zuvanich EG, Haghi KR, Morrison DC (2001) Commercial preparations of lipoteichoic acid contain endotoxin that contributes to activation of mouse macrophages in vitro. Infect Immun 69(2):751–757PubMed
37.
Hirschfeld M, Ma Y, Weis JH, Vogel SN, Weis JJ (2000) Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine toll-like receptor 2. J Immunol 165(2):618–622PubMed
38.
Takeuchi O, Hoshino K, Akira S (2000) Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J Immunol 165(10):5392–5396PubMed
39.
Bernheiden M, Heinrich IM, Minigo G, Schutt C, Stelter F, Freeman M, Golenbock D, Jack RS (2001) LBP, CD14, TLR4 and the murine innate immune response to a peritoneal Salmonella infection. J Endotoxin Res 7(6):447–450PubMed
40.
Okamura Y, Watari M, Jerud ES, Young DW, Ishizaka ST, Rose J, Chow JC, Strauss JF 3rd (2001) The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem 276(13):10229–10233PubMed
41.
Harter L, Mica L, Stocker R, Trentz O, Keel M (2004) Increased expression of toll-like receptor-2 and -4 on leukocytes from patients with sepsis. Shock 22(5):403–409PubMed
42.
Armstrong L, Medford AR, Hunter KJ, Uppington KM, Millar AB (2004) Differential expression of Toll-like receptor (TLR)-2 and TLR-4 on monocytes in human sepsis. Clin Exp Immunol 136(2):312–319PubMed
43.
Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4(7):499–511PubMed
44.
Iwami KI, Matsuguchi T, Masuda A, Kikuchi T, Musikacharoen T, Yoshikai Y (2000) Cutting edge: naturally occurring soluble form of mouse Toll-like receptor 4 inhibits lipopolysaccharide signaling. J Immunol 165(12):6682–6686PubMed
45.
Mitsuzawa H, Nishitani C, Hyakushima N, Shimizu T, Sano H, Matsushima N, Fukase K, Kuroki Y (2006) Recombinant soluble forms of extracellular TLR4 domain and MD-2 inhibit lipopolysaccharide binding on cell surface and dampen lipopolysaccharide-induced pulmonary inflammation in mice. J Immunol 177(11):8133–8139PubMed
46.
LeBouder E, Rey-Nores JE, Rushmere NK, Grigorov M, Lawn SD, Affolter M, Griffin GE, Ferrara P, Schiffrin EJ, Morgan BP, Labeta MO (2003) Soluble forms of Toll-like receptor (TLR)2 capable of modulating TLR2 signaling are present in human plasma and breast milk. J Immunol 171(12):6680–6689PubMed
47.
Liew FY, Xu D, Brint EK, O’Neill LA (2005) Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol 5(6):446–458PubMed
48.
Janssens S, Burns K, Vercammen E, Tschopp J, Beyaert R (2003) MyD88S, a splice variant of MyD88, differentially modulates NF-kappaB- and AP-1-dependent gene expression. FEBS Lett 548(1-3):103–107PubMed
49.
Schroder NW, Schumann RR (2005) Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis 5(3):156–164PubMed
50.
Smirnova I, Mann N, Dols A, Derkx HH, Hibberd ML, Levin M, Beutler B (2003) Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Natl Acad Sci U S A 100(10):6075–6080PubMed
51.
Lorenz E, Mira JP, Cornish KL, Arbour NC, Schwartz DA (2000) A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect Immun 68(11):6398–401PubMed
52.
Moore CE, Segal S, Berendt AR, Hill AV, Day NP (2004) Lack of association between Toll-like receptor 2 polymorphisms and susceptibility to severe disease caused by Staphylococcus aureus. Clin Diagn Lab Immunol 11(6):1194–1197PubMed
53.
Ogus AC, Yoldas B, Ozdemir T, Uguz A, Olcen S, Keser I, Coskun M, Cilli A, Yegin O (2004) The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease. Eur Respir J 23(2):219–223PubMed
54.
Bochud PY, Hawn TR, Aderem A (2003) Cutting edge: a Toll-like receptor 2 polymorphism that is associated with lepromatous leprosy is unable to mediate mycobacterial signaling. J Immunol 170(7):3451–3454PubMed
55.
Ben-Ali M, Barbouche MR, Bousnina S, Chabbou A, Dellagi K (2004) Toll-like receptor 2 Arg677Trp polymorphism is associated with susceptibility to tuberculosis in Tunisian patients. Clin Diagn Lab Immunol 11(3):625–626PubMed
56.
Hawn TR, Verbon A, Lettinga KD, Zhao LP, Li SS, Laws RJ, Skerrett SJ, Beutler B, Schroeder L, Nachman A, Ozinsky A, Smith KD, Aderem A (2003) A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease. J Exp Med 198(10):1563–1572PubMed
57.
Johnson CM, Lyle EA, Omueti KO, Stepensky VA, Yegin O, Alpsoy E, Hamann L, Schumann RR, Tapping RI (2007) Cutting edge: A common polymorphism impairs cell surface trafficking and functional responses of TLR1 but protects against leprosy. J Immunol 178(12):7520–7524PubMed
58.
Jouault T, Ibata-Ombetta S, Takeuchi O, Trinel PA, Sacchetti P, Lefebvre P, Akira S, Poulain D (2003) Candida albicans phospholipomannan is sensed through toll-like receptors. J Infect Dis 188(1):165–172PubMed
59.
Shoham S, Huang C, Chen JM, Golenbock DT, Levitz SM (2001) Toll-like receptor 4 mediates intracellular signaling without TNF-alpha release in response to Cryptococcus neoformans polysaccharide capsule. J Immunol 166(7):4620–4626PubMed
60.
Ozinsky A, Underhill DM, Fontenot JD, Hajjar AM, Smith KD, Wilson CB, Schroeder L, Aderem A (2000) The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci U S A 97(25):13766–13771PubMed
61.
Netea MG, Van Der Graaf CA, Vonk AG, Verschueren I, Van Der Meer JW, Kullberg BJ (2002) The role of toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis. J Infect Dis 185(10):1483–1489PubMed
62.
Dubourdeau M, Athman R, Balloy V, Huerre M, Chignard M, Philpott DJ, Latge JP, Ibrahim-Granet O (2006) Aspergillus fumigatus induces innate immune responses in alveolar macrophages through the MAPK pathway independently of TLR2 and TLR4. J Immunol 177(6):3994–4001PubMed
63.
Sachs J, Malaney P (2002) The economic and social burden of malaria. Nature 415(6872):680–685PubMed
64.
Greenwood BM, Bojang K, Whitty CJ, Targett GA (2005) Malaria. Lancet 365(9469):1487–1498PubMed
65.
Krishnegowda G, Hajjar AM, Zhu J, Douglass EJ, Uematsu S, Akira S, Woods AS, Gowda DC (2005) Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum: cell signaling receptors, glycosylphosphatidylinositol (GPI) structural requirement, and regulation of GPI activity. J Biol Chem 280(9):8606–8616PubMed
66.
Parroche P, Lauw FN, Goutagny N, Latz E, Monks BG, Visintin A, Halmen KA, Lamphier M, Olivier M, Bartholomeu DC, Gazzinelli RT, Golenbock DT (2007) Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9. Proc Natl Acad Sci USA 104(6):1919–1924PubMed
67.
Coban C, Ishii KJ, Kawai T, Hemmi H, Sato S, Uematsu S, Yamamoto M, Takeuchi O, Itagaki S, Kumar N, Horii T, Akira S (2005) Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J Exp Med 201(1):19–25PubMed
68.
Coban C, Ishii KJ, Uematsu S, Arisue N, Sato S, Yamamoto M, Kawai T, Takeuchi O, Hisaeda H, Horii T, Akira S (2007) Pathological role of Toll-like receptor signaling in cerebral malaria. Int Immunol 19(1):67–79PubMed
69.
Khor CC, Chapman SJ, Vannberg FO, Dunne A, Murphy C, Ling EY, Frodsham AJ, Walley AJ, Kyrieleis O, Khan A, Aucan C, Segal S, Moore CE, Knox K, Campbell SJ, Lienhardt C, Scott A, Aaby P, Sow OY, Grignani RT, Sillah J, Sirugo G, Peshu N, Williams TN, Maitland K, Davies RJ, Kwiatkowski DP, Day NP, Yala D, Crook DW, Marsh K, Berkley JA, O'Neill LA, Hill AV (2007) A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet 39(4):523–528PubMed
70.
Mockenhaupt FP, Cramer JP, Hamann L, Stegemann MS, Eckert J, Oh NR, Otchwemah RN, Dietz E, Ehrhardt S, Schroder NW, Bienzle U, Schumann RR (2006) Toll-like receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria. Proc Natl Acad Sci USA 103(1):177–182PubMed
71.
Finberg RW, Wang JP, Kurt-Jones EA (2007) Toll like receptors and viruses. Rev Med Virol 17(1):35–43PubMed
72.
Klinger JR, Sanchez MP, Curtin LA, Durkin M, Matyas B (1998) Multiple cases of life-threatening adenovirus pneumonia in a mental health care center. Am J Respir Crit Care Med 157(2):645–649PubMed
73.
Saito T, Gale M Jr (2007) Principles of intracellular viral recognition. Curr Opin Immunol 19(1):17–23PubMed
74.
Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, Matsui K, Tsujimura T, Takeda K, Fujita T, Takeuchi O, Akira S (2005) Cell type-specific involvement of RIG-I in antiviral response. Immunity 23(1):19–28PubMed
75.
Kurt-Jones EA, Popova L, Kwinn L, Haynes LM, Jones LP, Tripp RA, Walsh EE, Freeman MW, Golenbock DT, Anderson LJ, Finberg RW (2000) Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol 1(5):398–401PubMed
76.
Tulic MK, Hurrelbrink RJ, Prele CM, Laing IA, Upham JW, Le Souef P, Sly PD, Holt PG (2007) TLR4 polymorphisms mediate impaired responses to respiratory syncytial virus and lipopolysaccharide. J Immunol 179(1):132–40PubMed
77.
Compton T, Kurt-Jones EA, Boehme KW, Belko J, Latz E, Golenbock DT, Finberg RW (2003) Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2. J Virol 77(8):4588–4596PubMed
78.
Bieback K, Lien E, Klagge IM, Avota E, Schneider-Schaulies J, Duprex WP, Wagner H, Kirschning CJ, Ter Meulen V, Schneider-Schaulies S (2002) Hemagglutinin protein of wild-type measles virus activates toll-like receptor 2 signaling. J Virol 76(17):8729–8736PubMed
79.
Wang JP, Kurt-Jones EA, Shin OS, Manchak MD, Levin MJ, Finberg RW (2005) Varicella-zoster virus activates inflammatory cytokines in human monocytes and macrophages via Toll-like receptor 2. J Virol 79(20):12658–12666PubMed
80.
Kurt-Jones EA, Chan M, Zhou S, Wang J, Reed G, Bronson R, Arnold MM, Knipe DM, Finberg RW (2004) Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis. Proc Natl Acad Sci USA 101(5):1315–1320PubMed
81.
Cristofaro P, Opal SM (2006) Role of Toll-like receptors in infection and immunity: clinical implications. Drugs 66(1):15–29PubMed
82.
Bowie AG (2007) Translational mini-review series on Toll-like receptors: recent advances in understanding the role of Toll-like receptors in anti-viral immunity. Clin Exp Immunol 147(2):217–226PubMedCrossRef
83.
Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413(6857):732–738PubMed
84.
Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA (2004) Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med 10(12):1366–1373PubMed
85.
Town T, Jeng D, Alexopoulou L, Tan J, Flavell RA (2006) Microglia recognize double-stranded RNA via TLR3. J Immunol 176(6):3804–3812PubMed
86.
Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J (2005) Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437(7062):1167–1172PubMed
87.
Harte MT, Haga IR, Maloney G, Gray P, Reading PC, Bartlett NW, Smith GL, Bowie A, O'Neill LA (2003) The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defense. J Exp Med 197(3):343–351PubMed
88.
Stack J, Haga IR, Schroder M, Bartlett NW, Maloney G, Reading PC, Fitzgerald KA, Smith GL, Bowie AG (2005) Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence. J Exp Med 201(6):1007–1018PubMed
89.
Reinhart K, Karzai W (2001) Anti-tumor necrosis factor therapy in sepsis: update on clinical trials and lessons learned. Crit Care Med 29(7 Suppl):S121–S125PubMed
90.
Fisher CJ Jr, Dhainaut JF, Opal SM, Pribble JP, Balk RA, Slotman GJ, Iberti TJ, Rackow EC, Shapiro MJ, Greenman RL et al (1994) Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA 271(23):1836–1843PubMed
91.
Braisted AC, Oslob JD, Delano WL, Hyde J, McDowell RS, Waal N, Yu C, Arkin MR, Raimundo BC (2003) Discovery of a potent small molecule IL-2 inhibitor through fragment assembly. J Am Chem Soc 125(13):3714–3715PubMed
92.
Ii M, Matsunaga N, Hazeki K, Nakamura K, Takashima K, Seya T, Hazeki O, Kitazaki T, Iizawa Y (2006) A novel cyclohexene derivative, ethyl (6R)-6-[N-(2-Chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling. Mol Pharmacol 69(4):1288–1295PubMed
93.
Yamada M, Ichikawa T, Ii M, Sunamoto M, Itoh K, Tamura N, Kitazaki T (2005) Discovery of novel and potent small-molecule inhibitors of NO and cytokine production as antisepsis agents: synthesis and biological activity of alkyl 6-(N-substituted sulfamoyl)cyclohex-1-ene-1-carboxylate. J Med Chem 48(23):7457–7467PubMed
94.
Sha T, Sunamoto M, Kitazaki T, Sato J, Ii M, Iizawa Y (2007) Therapeutic effects of TAK-242, a novel selective Toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model. Eur J Pharmacol 571(2–3):231–239PubMed
95.
Mullarkey M, Rose JR, Bristol J, Kawata T, Kimura A, Kobayashi S, Przetak M, Chow J, Gusovsky F, Christ WJ, Rossignol DP (2003) Inhibition of endotoxin response by e5564, a novel Toll-like receptor 4-directed endotoxin antagonist. J Pharmacol Exp Ther 304(3):1093–1102PubMed
96.
Lynn M, Rossignol DP, Wheeler JL, Kao RJ, Perdomo CA, Noveck R, Vargas R, D’Angelo T, Gotzkowsky S, McMahon FG (2003) Blocking of responses to endotoxin by E5564 in healthy volunteers with experimental endotoxemia. J Infect Dis 187(4):631–639PubMed
97.
Lynn M, Wong YN, Wheeler JL, Kao RJ, Perdomo CA, Noveck R, Vargas R, D’Angelo T, Gotzkowsky S, McMahon FG, Wasan KM, Rossignol DP (2004) Extended in vivo pharmacodynamic activity of E5564 in normal volunteers with experimental endotoxemia. J Pharmacol Exp Ther 308(1):175–181PubMed
98.
Fort MM, Mozaffarian A, Stover AG, Correia Jda S, Johnson DA, Crane RT, Ulevitch RJ, Persing DH, Bielefeldt-Ohmann H, Probst P, Jeffery E, Fling SP, Hershberg RM (2005) A synthetic TLR4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease. J Immunol 174(10):6416–6423PubMed
99.
Meng G, Rutz M, Schiemann M, Metzger J, Grabiec A, Schwandner R, Luppa PB, Ebel F, Busch DH, Bauer S, Wagner H, Kirschning CJ (2004) Antagonistic antibody prevents Toll-like receptor 2-driven lethal shock-like syndromes. J Clin Invest 113(10):1473–1481PubMed
100.
Azoulay E, Delclaux C (2004) Is there a place for granulocyte colony-stimulating factor in non-neutropenic critically ill patients? Intensive Care Med 30(1):10–17PubMed
101.
Stephan F, Yang K, Tankovic J, Soussy CJ, Dhonneur G, Duvaldestin P, Brochard L, Brun-Buisson C, Harf A, Delclaux C (2002) Impairment of polymorphonuclear neutrophil functions precedes nosocomial infections in critically ill patients. Crit Care Med 30(2):315–322PubMed
102.
Ashkar AA, Yao XD, Gill N, Sajic D, Patrick AJ, Rosenthal KL (2004) Toll-like receptor (TLR)-3, but not TLR4, agonist protects against genital herpes infection in the absence of inflammation seen with CpG DNA. J Infect Dis 190(10):1841–1849PubMed
103.
Ambrus JL Sr, Chadha KC, Islam A, Akhter S, Ambrus JL Jr (2006) Treatment of viral and neoplastic diseases with double-stranded RNA derivatives and other new agents. Exp Biol Med (Maywood) 231(8):1283–1286
104.
Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S (2002) Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3(2):196–200PubMed
105.
Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, Lipford G, Bauer S (2002) Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 3(6):499PubMed
106.
107.
Martinez V, Molina JM, Scieux C, Ribaud P, Morfin F (2006) Topical imiquimod for recurrent acyclovir-resistant HSV infection. Am J Med 119(5):e9–e11PubMed
108.
Jones S, Kress D (2007) Treatment of molluscum contagiosum and herpes simplex virus cutaneous infections. Cutis 79(4 Suppl):11–17PubMed
109.
Arevalo I, Tulliano G, Quispe A, Spaeth G, Matlashewski G, Llanos-Cuentas A, Pollack H (2007) Role of imiquimod and parenteral meglumine antimoniate in the initial treatment of cutaneous leishmaniasis. Clin Infect Dis 44(12):1549–1554PubMed
110.
Harrison LI, Astry C, Kumar S, Yunis C (2007) Pharmacokinetics of 852A, an imidazoquinoline toll-like receptor 7-specific agonist, following intravenous, subcutaneous, and oral administrations in humans. J Clin Pharmacol 47(8):962–969PubMed
111.
Spaner DE, Masellis A (2007) Toll-like receptor agonists in the treatment of chronic lymphocytic leukemia. Leukemia 21(1):53–60PubMed
112.
Hammerbeck DM, Burleson GR, Schuller CJ, Vasilakos JP, Tomai M, Egging E, Cochran FR, Woulfe S, Miller RL (2007) Administration of a dual toll-like receptor 7 and toll-like receptor 8 agonist protects against influenza in rats. Antiviral Res 73(1):1–11PubMed
113.
Jennings GT, Bachmann MF (2007) Designing recombinant vaccines with viral properties: a rational approach to more effective vaccines. Curr Mol Med 7(2):143–155PubMed
114.
Halperin SA, Van Nest G, Smith B, Abtahi S, Whiley H, Eiden JJ (2003) A phase I study of the safety and immunogenicity of recombinant hepatitis B surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide adjuvant. Vaccine 21(19–20):2461–2467PubMed
115.
Cooper CL, Davis HL, Morris ML, Efler SM, Adhami MA, Krieg AM, Cameron DW, Heathcote J (2004) CPG 7909, an immunostimulatory TLR9 agonist oligodeoxynucleotide, as adjuvant to Engerix-B HBV vaccine in healthy adults: a double-blind phase I/II study. J Clin Immunol 24(6):693–701PubMed
116.
Baldridge JR, McGowan P, Evans JT, Cluff C, Mossman S, Johnson D, Persing D (2004) Taking a Toll on human disease: Toll-like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents. Expert Opin Biol Ther 4(7):1129–38PubMed
117.
Li XD, Sun L, Seth RB, Pineda G, Chen ZJ (2005) Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci U S A 102(49):17717–17722PubMed
118.
Reesink HW, Zeuzem S, Weegink CJ, Forestier N, van Vliet A, van de Wetering de Rooij J, McNair L, Purdy S, Kauffman R, Alam J, Jansen PL (2006) Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology 131(4):997–1002PubMed
119.
Hinrichsen H, Benhamou Y, Wedemeyer H, Reiser M, Sentjens RE, Calleja JL, Forns X, Erhardt A, Cronlein J, Chaves RL, Yong CL, Nehmiz G, Steinmann GG (2004) Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. Gastroenterology 127(5):1347–1355PubMed
120.
Lamarre D, Anderson PC, Bailey M, Beaulieu P, Bolger G, Bonneau P, Bos M, Cameron DR, Cartier M, Cordingley MG, Faucher AM, Goudreau N, Kawai SH, Kukolj G, Lagace L, LaPlante SR, Narjes H, Poupart MA, Rancourt J, Sentjens RE, St George R, Simoneau B, Steinmann G, Thibeault D, Tsantrizos YS, Weldon SM, Yong CL, Llinas-Brunet M (2003) An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 426(6963):186–189PubMed
Metadata
Title
Severe sepsis and Toll-like receptors
Authors
Hongmei Gao
Susannah K. Leaver
Anne Burke-Gaffney
Simon J. Finney
Publication date
01-02-2008
Publisher
Springer-Verlag
Published in
Seminars in Immunopathology / Issue 1/2008
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI
https://doi.org/10.1007/s00281-007-0101-4

Other articles of this Issue 1/2008

Seminars in Immunopathology 1/2008 Go to the issue

Review

Role of TLRs/MyD88 in host resistance and pathogenesis during protozoan infection: lessons from malaria

Introduction

TLRs in disease

Review

TLR2 in murine atherosclerosis

Review

The “polarizing–tolerizing” mechanism of intestinal epithelium: its relevance to colonic homeostasis

Review

Toll like receptor-5: protecting the gut from enteric microbes

Review

Defining a role for ambient TLR ligand exposures in the genesis and prevention of allergic diseases
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits