961
Views
105
CrossRef citations to date
0
Altmetric
Review

Pattern recognition receptors: sentinels in innate immunity and targets of new vaccine adjuvants

Pages 237-256 | Published online: 09 Jan 2014

References

  • Kumar H, Kawai T, Akira S. Pathogen recognition in the innate immune response. Biochem. J.420, 1–16 (2009).
  • Kumar H, Kawai T, Akira S. Pathogen recognition by the innate immune system. Int. Rev. Immunol.30, 16–34 (2011).
  • Palm NW, Medzhitov R. Pattern recognition receptors and control of adaptive immunity. Immunol. Rev.227, 221–233 (2009).
  • Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science327, 291–295 (2010).
  • Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat. Immunol.5, 987–995 (2004).
  • Jung D, Alt FW. Unravelling V(D)J recombination: insights into gene regulation. Cell116, 299–311 (2004).
  • Lotze MT, Zeh HJ, Rubartelli A et al. The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunol. Rev.220, 60–81 (2007).
  • Bell JK, Mullen GE, Leifer CA, Mazzoni A, Davies DR, Segal DM. Leucine-rich repeats and pathogen recognition in Toll-like receptors. Trends Immunol.24, 528–533 (2003).
  • O’Neill LAJ, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat. Rev. Immunol.7, 353–364 (2007).
  • Kumagai Y, Takeuchi O, Akira S. Pathogen recognition by innate receptors. J. Infect. Chemother.14, 86–92 (2008).
  • Aliprantis AO, Yang RB, Mark MR et al. Cell activation and apoptosis by bacterial lipoproteins through Toll-like receptor-2. Science285, 736–739 (1999).
  • Hirschfeld M, Kirschning CJ, Schwandner R et al. Cutting edge: inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by Toll-like receptor 2. J. Immunol.163, 2382–2386 (1999).
  • Hasebe A, Mu HH, Washburn LR et al. Inflammatory lipoproteins purified from a toxigenic and arthritogenic strain of Mycoplasma arthritidis are dependent on Toll-like receptor 2 and CD14. Infect. Immun.75, 1820–1826 (2007).
  • López M, Sly LM, Luu Y, Young D, Cooper H, Reiner NE. The 19-kDa Mycobacterium tuberculosis protein induces macrophage apoptosis through Toll-like receptor-2. J. Immunol.170, 2409–2416 (2003).
  • Lien E, Sellati TJ, Yoshimura A et al. Toll-like receptor 2 functions as a pattern recognition receptor for diverse bacterial products. J. Biol. Chem.274, 33419–33425 (1999).
  • Takeuchi O, Kawai T, Mühlradt PF et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int. Immunol.13, 933–940 (2001).
  • Takeuchi O, Kaufmann A, Grote K et al. Cutting edge: preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a Toll-like receptor 2- and MyD88-dependent signaling pathway. J. Immunol.164, 554–557 (2000).
  • Dziarski R, Gupta D. Staphylococcus aureus peptidoglycan is a Toll-like receptor 2 activator: a reevaluation. Infect. Immun.73, 5212–5216 (2005).
  • Ozinsky A, Underhill DM, Fontenot JD et al. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors. Proc. Natl Acad. Sci. USA97, 13766–13771 (2000).
  • Schwandner R, Dziarski R, Wesche H, Rothe M, Kirschning CJ. Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by Toll-like receptor 2. J. Biol. Chem.274, 17406–17409 (1999).
  • Schröder NW, Morath S, Alexander C et al. Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor (TLR)-2, lipopolysaccharide-binding protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved. J. Biol. Chem.278, 15587–15594 (2003).
  • Levitz SM. Interactions of Toll-like receptors with fungi. Microbes Infect.6, 1351–1355 (2004).
  • Gantner BN, Simmons RM, Canavera SJ, Akira S, Underhill DM. Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J. Exp. Med.197, 1107–1117 (2003).
  • Means TK, Lien E, Yoshimura A, Wang S, Golenbock DT, Fenton MJ. The CD14 ligands lipoarabinomannan and lipopolysaccharhide differ in their requirement for Toll-like receptors. J. Immunol.163, 6748–6755 (1999).
  • Ropert C, Gazzinelli RT. Regulatory role of Toll-like receptor 2 during infection with Trypanosoma cruzi. J. Endotoxin Res.10, 425–430 (2004).
  • Bieback K, Lien E, Klagge IM et al. Hemagglutinin protein of wild-type measles virus activates Toll-like receptor 2 signaling. J. Virol.76, 8729–8736 (2002).
  • Netea MG, Kullberg BJ, Galama JM, Stalenhoef AF, Dinarello CA, Van der Meer JW. Non-LPS components of Chlamydia pneumoniae stimulate cytokine production through Toll-like receptor 2-dependent pathways. Eur. J. Immunol.32, 1188–1195 (2002).
  • Kurt-Jones EA, Chan M, Zhou S et al. Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis. Proc. Natl Acad. Sci. USA101, 1315–1320 (2004).
  • Wang JP, Kurt-Jones EA, Shin OS, Manchak MD, Levin MJ, Finberg RW. Varicella-zoster virus activates inflammatory cytokines in human monocytes and macrophages via Toll-like receptor 2. J. Virol.79, 12658–12666 (2005).
  • Takeuchi O, Sato S, Horiuchi T et al. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol.169, 10–14 (2002).
  • Hoebe K, Georgel P, Rutschmann S et al. CD36 is a sensor of diacylglycerides. Nature433, 523–527 (2005).
  • Barbalat R, Lau L, Locksley RM, Barton GM. Toll-like receptor 2 on inflammatory monocytes induces Type 1 interferon in response to viral but not bacterial ligands. Nat. Immunol.10, 1200–1207 (2009).
  • Poltorak A, He X, Smirnova I et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in TLR4 gene. Science282, 2085–2088 (1998).
  • Hoshino K, Takeuchi O, Kawai T et al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the LPS gene product. J. Immunol.162, 3749–3752 (1999).
  • Kim HM, Park BS, Kim JI et al. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell130, 906–917 (2007).
  • Akashi-Takamura S, Miyake K. TLR accessory molecules. Curr. Opin. Immunol.20, 420–425 (2008).
  • Lu YC, Yeh WC, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine42, 145–151 (2008).
  • Gazzinelli RT, Ropert C, Campos MA. Role of the Toll/interleukin-1 receptor signaling pathway in host resistance and pathogenesis during infection with protozoan parasites. Immunol. Rev.201, 9–25 (2004).
  • Kurt-Jones EA, Popova L, Kwinn L et al. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat. Immunol.1, 398–401 (2000).
  • Burzyn D, Rassa JC, Kim D, Nepomnaschy I, Ross SR, Piazzon I. Toll-like receptor 4-dependent activation of dendritic cells by a retrovirus. J. Virol.78, 576–584 (2004).
  • Bernatoniene J, Zhang Q, Dogan S, Mitchell TJ, Paton JC, Finn A. Induction of CC and CXC chemokines in human antigen-presenting dendritic cells by the pneumococcal proteins pneumolysin and CbpA, and the role played by Toll-like receptor 4, NF-κB, and mitogen-activated protein kinases. J. Infect. Dis.198, 1823–1833 (2008).
  • Kawasaki K, Akashi S, Shimazu R, Yoshida T, Miyake K, Nishijima M. Mouse Toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. J. Biol. Chem.275, 2251–2254 (2000).
  • Mato-Haro V, Cekic C, Martin M, Chilton PM, Casella CR, Mitchell TC. The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science316, 1628–1632 (2007).
  • Hayashi F, Smith KD, Ozinsky A et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature410, 1099–1103 (2001).
  • Smith KD, Andersen-Nissen E, Hayashi F et al. Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility. Nat. Immunol.4, 1247–1253 (2003). Erratum in: Nat. Immunol.5, 451 (2004).
  • Yarovinsky F, Zhang D, Andersen JF et al. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science308, 1626–1629 (2005).
  • Lauw FN, Caffrey DR, Golenbock DT. Of mice and man: TLR11 (finally) finds profilin. Trends Immunol.26, 509–511 (2005).
  • Zhang D, Zhang G, Hayden MS et al. A Toll-like receptor that prevents infection by uropathogenic bacteria. Science303, 1522–1526 (2004).
  • Botos I, Liu L, Wang Y, Segal DM, Davies DR. The Toll-like receptor 3:dsRNA signaling complex. Biochim. Biophys. Acta1789, 667–674 (2009).
  • Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature413, 732–73 8 (2001).
  • Groskreutz DJ, Monick MM, Powers LS, Yarovinsky TO, Look DC, Hunninghake GW. Respiratory syncytial virus induces TLR3 protein and protein kinase R, leading to increased double-stranded RNA responsiveness in airway epithelial cells. J. Immunol.176, 1733–1740 (2006).
  • Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat. Med.10, 1366–1373 (2004).
  • Hardarson HS, Baker JS, Yang Z et al. Toll-like receptor 3 is an essential component of the innate stress response in virus-induced cardiac injury. Am. J. Physiol. Heart Circ. Physiol.292, H251–H258 (2007).
  • Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science303, 1529–1531 (2004).
  • Heil F, Hemmi H, Hochrein H et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science303, 1526–1529 (2004).
  • Hemmi H, Kaisho T, Takeuchi O et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol.3, 196–200 (2002).
  • Heil F, Ahmad-Nejad P, Hemmi H et al. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur. J. Immunol.33, 2987–2997 (2003).
  • Hemmi H, Takeuchi O, Kawai T et al. A Toll-like receptor recognizes bacterial DNA. Nature408, 740–745 (2000).
  • Klinman DM, Yi AK, Beaucage SL, Conover J, Krieg AM. CpG motifs present in bacterial DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon γ. Proc. Natl Acad. Sci. USA93, 2879–2883 (1996).
  • Krug A, Luker GD, Barchet W, Leib DA, Akira S, Colonna M. Herpes simplex virus Type 1 activates murine natural interferon-producing cells through Toll-like receptor 9. Blood103, 1433–1437 (2004).
  • Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A. Toll-like receptor 9-mediated recognition of herpes simplex virus-2 by plasmacytoid dendritic cells. J. Exp. Med.198, 513–520 (2003).
  • Krug A, French AR, Barchet W et al. TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity21, 107–119 (2004).
  • Coban C, Ishii KJ, Kawai T et al. Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J. Exp. Med.201, 19–25 (2005).
  • Hemmi H, Akira S. TLR signaling and the function of dendritic cells. Chem. Immunol. Allergy86, 120–135 (2005).
  • Kawai T, Akira S. TLR signaling. Semin. Immunol.19, 24–32 (2007).
  • Akira S, Takeda K. Toll-like receptor signalling. Nat. Rev. Immunol.4, 499–511 (2004).
  • O’Neill LAJ. How Toll-like receptors signal: what we know and what we don’t know. Curr. Opin. Immunol.18, 3–9 (2006).
  • Yamamoto M, Takeda K. Current views of Toll-like receptor signaling pathways. Gastroenterol. Res. Pract.2010, 240365 (2010).
  • Takeda K, Akira S. Toll-like receptors in innate immunity. Int. Immunol.17, 1–14 (2005).
  • Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol.11, 373–384 (2010).
  • Kawagoe T, Sato S, Jung A et al. Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling. J. Exp. Med.204, 1013–1024 (2007).
  • Li S, Strelow A, Fontana EJ, Wesche H. IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc. Natl Acad. Sci. USA99, 5567–5572 (2002).
  • Kawagoe T, Sato S, Matsushita K et al. Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nat. Immunol.9, 684–691 (2008).
  • Keating SE, Maloney GM, Moran EM, Bowie AG. IRAK-2 participates in multiple Toll-like receptor signaling pathways to NFkB via activation of TRAF6 ubiquitination. J. Biol. Chem.282, 33435–33443 (2007).
  • Lamothe B, Besse A, Campos AD, Webster WK, Wu H, Darnay BG. Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of IkB kinase activation. J. Biol. Chem.282, 4102–4112 (2007).
  • Deng L, Wang C, Spencer E et al. Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell103, 351–361 (2000).
  • Fan Y, Yu Y, Shi Y et al. Lysine 63-linked polyubiquitination of TAK1 at lysine 158 is required for tumor necrosis factor α- and interleukin-1β-induced IKK/NF-kB and JNK/AP-1 activation. J. Biol. Chem.285, 5347–5360 (2010).
  • Wu CJ, Conze DB, Li T, Srinivasula SM, Ashwell JD. Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kB activation. Nat. Cell Biol.8, 398–406 (2006).
  • Bhoj VG, Chen ZJ. Ubiquitylation in innate and adaptive immunity. Nature458, 430–437 (2009).
  • Takaoka A, Yanai H, Kondo S et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature434, 243–249 (2005).
  • Balkhi MY, Fitzgerald KA, Pitha PM. Functional regulation of MyD88-activated interferon regulatory factor 5 by K63-linked polyubiquitination. Mol. Cell Biol.28, 7296–7308 (2008).
  • Nagpal K, Plantinga TS, Wong J et al. A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of MyD88 binding and reduced TLR2/TLR4 signaling. J. Biol. Chem.284, 25742–25748 (2009).
  • Fitzgerald KA, Palsson-McDermott EM, Bowie AG et al. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature413, 78–83 (2001).
  • Verstak B, Nagpal K, Bottomley SP, Golenbock DT, Hertzog PJ, Mansell A. MyD88 adapter-like (Mal)/TIRAP interaction with TRAF6 is critical for TLR2- and TLR4-mediated NF-kB proinflammatory responses. J. Biol. Chem.284, 24192–24203 (2009).
  • Kawai T, Sato S, Ishii KJ et al. Interferon-a induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat. Immunol.5, 1061–1068 (2004).
  • Uematsu S, Sato S, Yamamoto M et al. Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-a induction. J. Exp. Med.201, 915–923 (2005).
  • Hoshino K, Sugiyama T, Matsumoto M et al. IκB kinase-α is critical for interferon-α production induced by Toll-like receptors 7 and 9. Nature440, 949–953 (2006).
  • Oganesyan G, Saha SK, Guo B et al. Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature439, 208–211 (2006).
  • Sharma S, tenOever BR, Grandvaux N, Zhou GP, Lin R, Hiscott J. Triggering the interferon antiviral response through an IKK-related pathway. Science300, 1148–1151 (2003).
  • tenOever BR, Sharma S, Zou W et al. Activation of TBK1 and IKKε kinases by vesicular stomatitis virus infection and the role of viral ribonucleoprotein in the development of interferon antiviral immunity. J. Virol.78, 10636–10649 (2004).
  • Fitzgerald KA, McWhirter SM, Faia KL et al. IKKε and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol.4, 491–496 (2003).
  • Oshiumi H, Matsumoto M, Funami K, Akazawa T, Seya T. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-β induction. Nat. Immunol.4, 161–167 (2003).
  • Sato S, Sugiyama M, Yamamoto M et al. Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kB and IFN-regulatory factor-3, in the Toll-like receptor signaling. J. Immunol.171, 4304–4310 (2003).
  • Ermolaeva MA, Michallet MC, Papadopoulou N et al. Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses. Nat. Immunol.9, 1037–1046 (2008).
  • Chang M, Jin W, Sun SC. Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production. Nat. Immunol.10, 1089–1095 (2009).
  • Fitzgerald KA, Rowe DC, Barnes BJ et al. LPS-TLR4 signaling to IRF-3/7 and NF-kB involves the Toll adapters TRAM and TRIF. J. Exp. Med.198, 1043–1055 (2003).
  • Yamamoto M, Sato S, Hemmi H et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat. Immunol.4, 1144–1150 (2003).
  • Franchi L, Warner N, Viani K, Nuñez G. Function of Nod-like receptors in microbial recognition and host defense. Immunol. Rev.227, 106–128 (2009).
  • Kanneganti TD, Lamkanfi M, Núñez G. Intracellular NOD-like receptors in host defense and disease. Immunity27, 549–559 (2007).
  • Girardin SE, Boneca IG, Carneiro LA et al. Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science300, 1584–1587 (2003).
  • Inohara N, Ogura Y, Fontalba A et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn’s disease. J. Biol. Chem.278, 5509–5512 (2003).
  • Viala J, Chaput C, Boneca IG et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat. Immunol.5, 1166–1174 (2004).
  • Zilbauer M, Dorrell N, Elmi A et al. A major role for intestinal epithelial nucleotide oligomerization domain 1 (NOD1) in eliciting host bactericidal immune responses to Campylobacter jejuni. Cell Microbiol.9, 2404–2416 (2007).
  • Opitz B, Förster S, Hocke AC et al. Nod1-mediated endothelial cell activation by Chlamydophila pneumoniae. Circ. Res.96, 319–326 (2005).
  • Kim JG, Lee SJ, Kagnoff MF. Nod1 is an essential signal transducer in intestinal epithelial cells infected with bacteria that avoid recognition by Toll-like receptors. Infect. Immun.72, 1487–1495 (2004).
  • Opitz B, Püschel A, Schmeck B et al. Nucleotide-binding oligomerization domain proteins are innate immune receptors for internalized Streptococcus pneumoniae. J. Biol. Chem.279, 36426–36432 (2004).
  • Ferwerda G, Girardin SE, Kullberg BJ et al. NOD2 and Toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis. PLoS Pathog.1, 279–285 (2005).
  • Girardin SE, Boneca IG, Viala J et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J. Biol. Chem.278, 8869–8872 (2003).
  • Inohara N, Koseki T, Lin J et al. An induced proximity model for NF-κB activation in the Nod1/RICK and RIP signaling pathways. J. Biol. Chem.275(36), 27823–27831 (2000).
  • Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-κB. J. Biol. Chem.276, 4812–4818 (2001).
  • Hasegawa M, Fujimoto Y, Lucas PC et al. A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-κB activation. EMBO J.27, 373–383 (2008).
  • da Silva Correia J, Miranda Y, Leonard N, Hsu J, Ulevitch RJ. Regulation of Nod1-mediated signaling pathways. Cell Death Differ.14, 830–839 (2007).
  • Windheim M, Lang C, Peggie M, Plater LA, Cohen P. Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide. Biochem. J.404, 179–190 (2007).
  • Silva GK, Gutierrez FR, Guedes PM et al. Cutting edge: nucleotide-binding oligomerization domain 1-dependent responses account for murine resistance against Trypanosoma cruzi infection. J. Immunol.184, 1148–1152 (2010).
  • Watanabe T, Asano N, Fichtner-Feigl S et al. NOD1 contributes to mouse host defense against Helicobacter pylori via induction of Type 1 IFN and activation of the ISGF3 signaling pathway. J. Clin. Invest.120, 1645–1662 (2010).
  • Sabbah A, Chang TH, Harnack R et al. Activation of innate immune antiviral responses by Nod2. Nat. Immunol.10, 1073–1080 (2009).
  • Shaw MH, Reimer T, Sánchez-Valdepeñas C et al. T cell-intrinsic role of Nod2 in promoting Type 1 immunity to Toxoplasma gondii. Nat. Immunol.10, 1267–1274 (2009).
  • Pandey AK, Yang Y, Jiang Z et al. NOD2, RIP2 and IRF5 play a critical role in the Type 1 interferon response to Mycobacterium tuberculosis. PLoS Pathog.5, e100050 (2009).
  • Kim YG, Kamada N, Shaw MH et al. The Nod2 sensor promotes intestinal pathogen eradication via the chemokine CCL2-dependent recruitment of inflammatory monocytes. Immunity34, 769–780 (2011).
  • Davis KM, Nakamura S, Weiser JN. Nod2 sensing of lysozyme-digested peptidoglycan promotes macrophage recruitment and clearance of S. pneumoniae colonization in mice. J. Clin. Invest.121, 3666–3676 (2011).
  • Nakamura S, Davis KM, Weiser JN. Synergistic stimulation of Type 1 interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice. J. Clin. Invest.121, 3657–3665 (2011).
  • Franchi L, Eigenbrod T, Muñoz-Planillo R, Nuñez G. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat. Immunol.10, 241–247 (2009).
  • Lamkanfi M, Dixit VM. Inflammasomes: guardians of cytosolic sanctity. Immunol. Rev.227, 95–105 (2009).
  • Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu. Rev. Immunol.27, 229–265 (2009).
  • Schroder K, Tschopp J. The inflammasomes. Cell140, 821–832 (2010).
  • Mehta VB, Hart J, Wewers MD. ATP-stimulated release of interleukin (IL)-1β and IL-18 requires priming by lipopolysaccharide and is independent of caspase-1 cleavage. J. Biol. Chem.276, 3820–3826 (2001).
  • Mariathasan S, Weiss DS, Newton K et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature440, 228–232 (2006).
  • Martinon F, Agostini L, Meylan E, Tschopp J. Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Curr. Biol.14, 1929–1934 (2004).
  • Shio MT, Eisenbarth SC, Savaria M et al. Malarial hemozoin activates the NLRP3 inflammasome through Lyn and SYK kinases. PLoS Pathog.5, e1000559 (2009).
  • Kanneganti TD, Ozören N, Body-Malapel M et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/NALP3. Nature440, 233–236 (2006).
  • Muruve DA, Petrilli V, Zaiss AK et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature452, 103–107 (2008).
  • Kanneganti TD, Body-Malapel M, Amer A et al. Critical role for Cryopyrin/NALP3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J. Biol. Chem.281, 36560–36568 (2006).
  • Allen IC, Scull MA, Moore CB et al. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity30, 556–565 (2009).
  • Barlan AU, Griffin TM, McGuire KA, Wiethoff CM. Adenovirus membrane penetration activates the NLRP3 inflammasome. J. Virol.85, 146–155 (2011).
  • Pang IK, Iwasaki A. Inflammasomes as mediators of immunity against influenza virus. Trends Immunol.32, 34–41 (2011).
  • Rajan JV, Rodriguez D, Miao EA, Aderem A. The NLRP3 inflammasome detects encephalomyelitis virus and vesicular stomatitis virus infection. J. Virol.85, 4167–4172 (2011).
  • Komune N, Ichinohe T, Ito M, Yanagi Y. Measles virus V protein inhibits NLRP3 inflammasome-mediated IL-1β secretion. J. Virol.85(24), 13019–13026 (2011).
  • Delaloye J, Roger T, Steiner-Tardivel QG et al. Innate immune sensing of modified vaccinia virus Ankara (MVA) is mediated by TLR2-TLR6, MDA-5 and the NALP3 inflammasome. PLoS Pathog.5, e1000480 (2009).
  • Meixenberger K, Pache F, Eitel J et al.Listeria monocytogenes-infected human peripheral blood mononuclear cells produce IL-1β, depending on listeriolysin O and NLRP3. J. Immunol.184, 922–930 (2010).
  • Gurcel L, Abrami L, Girardin S, Tschopp J, van der Goot FG. Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival. Cell126, 1135–1145 (2006).
  • Craven RR, Gao X, Allen IC et al.Staphylococcus aureus α-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells. PLoS One4, e7446 (2009).
  • Ichinohe T, Pang IK, Iwasaki A. Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nat. Immunol.11, 404–410 (2010).
  • Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature40, 237–241 (2006).
  • Duewell P, Kono H, Rayner KJ et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature464, 1357–1361 (2010).
  • Rajamäki K, Lappalainen J, Oörni K et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One5, e11765 (2010).
  • Cassel SL, Eisenbarth SC, Iyer SS et al. The NALP3 inflammasome is essential for the development of silicosis. Proc. Natl Acad. Sci. USA105, 9035–9040 (2008).
  • Dostert C, Pétrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through NALP3 inflammasome sensing of asbestos and silica. Science320, 674–677 (2008).
  • Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA. Crucial role for the NALP3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature453, 1122–1126 (2008).
  • Kool M, Pétrilli V, De Smedt T et al. Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J. Immunol.181, 3755–3759 (2008).
  • Li H, Willingham SB, Ting JP, Re F. Cutting edge: inflammasome activation by alum and alum’s adjuvant effect are mediated by NLRP3. J. Immunol.181, 17–21 (2008).
  • Halle A, Hornung V, Petzold GC et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-b. Nat. Immunol.9, 857–865 (2008).
  • Pétrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ.14, 1583–1589 (2007).
  • Pelegrin P, Surprenant A. Pannexin-1 mediates large pore formation and interleukin-1β release by the ATP-gated P2X7 receptor. EMBO J.25, 5071–5082 (2006).
  • Kanneganti TD, Lamkanfi M, Kim YG et al. Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling. Immunity26, 433–443 (2007).
  • Martinon F. Signaling by ROS drives inflammasome activation. Eur. J. Immunol.40, 616–619 (2010).
  • Hornung V, Latz E. Critical functions of priming and lysosomal damage for NLRP3 activation. Eur. J. Immunol.40, 620–623 (2010).
  • Kumar H, Kumagai Y, Tsuchida T et al. Involvement of the NLRP3 inflammasome in innate and humoral adaptive immune responses to fungal β-glucan. J. Immunol.183, 8061–8067 (2009).
  • Lamkanfi M, Malireddi RK, Kanneganti TD. Fungal zymosan and mannan activate the cryopyrin inflammasome. J. Biol. Chem.284, 20574–20581 (2009).
  • Gross O, Poeck H, Bscheider M et al. SYK kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature459, 433–436 (2009).
  • Sutterwala FS, Flavell RA. NLRC4/IPAF: a CARD carrying member of the NLR family. Clin. Immunol.130, 2–6 (2009).
  • Mariathasan S, Newton K, Monack DM et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature430, 213–218 (2004).
  • Sutterwala FS, Mijares LA, Li L, Ogura Y, Kazmierczak BI, Flavell RA. Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome. J. Exp. Med.204, 3235–3245 (2007).
  • Suzuki T, Franchi L, Toma C et al. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog.3, e111 (2007).
  • Zamboni DS, Kobayashi KS, Kohlsdorf T et al. The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat. Immunol.7, 318–325 (2006).
  • Miao EA, Mao DP, Yudkovsky N et al. Innate immune detection of the Type 3 secretion apparatus through the NLRC4 inflammasome. Proc. Natl Acad. Sci. USA107, 3076–3080 (2010).
  • Warren SE, Mao DP, Rodriguez AE, Miao EA, Aderem A. Multiple Nod-like receptors activate caspase 1 during Listeria monocytogenes infection. J. Immunol.180, 7558–7564 (2008).
  • Lightfield KL, Persson J, Trinidad NJ et al. Differential requirements for NAIP5 in activation of the NLRC4 inflammasome. Infect. Immun.79, 1606–1614 (2011).
  • Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell10, 417–426 (2002).
  • Tschopp J, Martinon F, Burns K. NALPs: a novel protein family involved in inflammation. Nat. Rev. Mol. Cell Biol.4, 95–104 (2003).
  • Faustin B, Lartigue L, Bruey JM et al. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol. Cell25, 713–724 (2007).
  • Boyden ED, Dietrich WF. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat. Genet.38, 240–244 (2006).
  • Roberts TL, Idris A, Dunn JA et al. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science323, 1057–1060 (2009).
  • Bürckstümmer T, Baumann C, Blüml S et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat. Immunol.10, 266–272 (2009).
  • Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature458, 509–513 (2009).
  • Hornung V, Ablasser A, Charrel-Dennis M et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature458, 514–518 (2009).
  • Rathinam VA, Jiang Z, Waggoner SN et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat. Immunol.11, 395–402 (2010).
  • Fernandes-Alnemri T, Yu JW, Juliana C et al. The AIM2 inflammasome is critical for innate immunity to Francisella tularensis. Nat. Immunol.11, 385–393 (2010).
  • Jones JW, Kayagaki N, Broz P et al. Absent in melanoma 2 is required for innate immune recognition of Francisella tularensis. Proc. Natl Acad. Sci. USA107, 9771–9776 (2010).
  • Warren SE, Armstrong A, Hamilton MK et al. Cutting edge: Cytosolic bacterial DNA activates the inflammasome via Aim2. J. Immunol.185, 818–821 (2010).
  • Barber GN. Innate immune DNA sensing pathways: STING, AIMII and the regulation of interferon production and inflammatory responses. Curr. Opin. Immunol.23, 10–20 (2011).
  • Yang P, An H, Liu X et al. The cytosolic nucleic acid sensor LRRFIP1 mediates the production of Type 1 interferon via a β-catenin-dependent pathway. Nat. Immunol.11, 487–494 (2010).
  • Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int. Immunol.21, 317–337 (2009).
  • Creagh EM, O’Neill LA. TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity. Trends Immunol.27, 352–357 (2006).
  • Kato H, Takeuchi O, Sato S et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature441, 101–105 (2006).
  • Wilkins C, Gale M. Recognition of viruses by cytoplasmic sensors. Curr. Opin. Immunol.22, 41–47 (2010).
  • Kawai T, Takahashi K, Sato S et al. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated Type 1 interferon induction. Nat. Immunol.6, 981–988 (2005).
  • Michallet MC, Meylan E, Ermolaeva MA et al. TRADD protein is an essential component of the RIG-like helicase antiviral pathway. Immunity28, 651–661 (2008).
  • Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature455, 674–678 (2008).
  • Satoh T, Kato H, Kumagai Y et al. LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. Proc. Natl Acad. Sci. USA107, 1512–1517 (2010).
  • Pichlmair A, Schulz O, Tan CP et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5´-phosphates. Science314, 997–1001 (2006).
  • Kato H, Takeuchi O, Mikamo-Satoh E et al. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J. Exp. Med.205, 1601–1610 (2008).
  • Bafica A, Scanga CA, Feng CG, Leifer C, Cheever A, Sher A. TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis. J. Exp. Med.202, 1715–1724 (2005).
  • Sorensen LN, Reinert LS, Malmgaard L, Bartholdy C, Thomsen AR, Paludan SR. TLR2 and TLR9 synergistically control herpes simplex virus infection in the brain. J. Immunol.181, 8604–8612 (2008).
  • Bafica A, Santiago HC, Goldszmid R, Ropert C, Gazzinelli RT, Sher A. Cutting edge: TLR9 and TLR2 signaling together account for MyD88-dependent control of parasitemia in Trypanosoma cruzi infection. J. Immunol.177, 3515–3519 (2006).
  • Gautier G, Humbert M, Deauvieau F et al. A Type 1 interferon autocrine-paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells. J. Exp. Med.210, 1435–1446 (2005).
  • Napolitani G, Rinaldi A, Bertoni F, Sallustro F, Lanzavecchia A. Selected Toll-like receptor agonist combinations synergistically trigger a T helper Type 1-polarizing program in dendritic cells. Nat. Immunol.6, 769–776 (2005).
  • Roelofs MF, Joosten LAB, Abdollahi-Roodsaz S. The expression of Toll-like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of Toll-like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells. Arthritis Rheum.52, 2313–2322 (2005).
  • Krummen M, Balkow S, Shen L et al. Release of IL-12 by dendritic cells activated by TLR ligation is dependent on MyD88 signaling, whereas TRIF signaling is indispensable for TLR synergy. J. Leukoc. Biol.88, 189–199 (2010).
  • Makela SM, Stregnell M, Pietila TE, Osterland P, Julkunen I. Multiple signalling pathways contribute to synergistic TLR ligand-dependent cytokine gene expression in human monocyte-derived macrophages and dendritic cells. J. Leuk. Biol.85, 664–672 (2009).
  • Bohnenkamp HR, Papazisis KT, Burchell JM, Taylor-Papadimitriou J. Synergism of Toll-like receptor-induced interleukin-12p70 secretion by monocyte-derived dendritic cells is mediated through p38 MAPK and lowers the threshold of T-helper cell Type 1 responses. Cell. Immunol.247, 72–84 (2007).
  • Warger T, Osterloh P, Rechtsteiner G et al. Synergistic activation of dendritic cells by combined Toll-like receptor ligation induces superior CTL responses in vivo. Blood108, 544–550 (2006).
  • Mitchell D, Yong M, Schroder W, Black M, Tirrell M, Olive C. Dual stimulation of MyD88-dependent Toll-like receptors induces synergistically enhanced production of inflammatory cytokines in murine bone marrow-derived dendritic cells. J. Infect. Dis.202, 318–329 (2010).
  • Vanhoutte F, Paget C, Breuilh L et al. Toll-like receptor (TLR)2 and TLR3 synergy and cross-inhibition in murine myeloid dendritic cells. Immunol. Lett.116, 86–94 (2008).
  • Hirata N, Yanagawa Y, Ebihara T et al. Selective synergy in anti-inflammatory cytokine production upon cooperated signalling via TLR4 and TLR2 in murine conventional dendritic cells. Mol. Immunol.45, 2734–2742 (2008).
  • Raman VS, Bhatia A, Picone A et al. Applying TLR synergy in immunotherapy: implications in cutaneous leishmaniasis. J. Immunol.185, 1701–1710 (2010).
  • Zhu Q, Egelston C, Gagnon S et al. Using 3 TLR ligands as a combination adjuvant induces qualitative changes in T cell responses needed for antiviral protection in mice. J. Clin. Invest.120, 607–616 (2010).
  • Chen WH, Basu S, Bhattacharjee AK, Cross AS. Enhanced antibody responses to a detoxified lipopolysaccharide-group B meningococcal outer membrane protein vaccine are due to synergistic engagement of Toll-like receptors. Innate Immun.16, 322–332 (2010).
  • Triozzi PL, Aldrich W, Ponnazhagan S. Regulation of the activity of an adeno-associated virus vector cancer vaccine administered with synthetic Toll-like receptor agonists. Vaccine28, 7837–7843 (2010).
  • Ghosh TK, Mickelson DJ, Solberg JC, Lipson KE, Inglefield JR, Alkan SS. TLR–TLR cross talk in human PBMC resulting in synergistic and antagonistic regulation of type-1 and 2 interferons, IL-12 and TNF-α. Int. Immunopharmacol.7, 1111–1121 (2007).
  • Bagchi A, Herrup EA, Warren HS et al. MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists. J. Immunol.178, 1164–1171 (2007).
  • Zhu Q, Egelston C, Vivekanandham A et al. Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: implications for vaccines. Proc. Natl Acad. Sci. USA105, 16260–16265 (2008).
  • Trincheri G, Sher, A. Cooperation of Toll-like receptor signals in innate immune defence. Nat. Rev. Immunol.7, 179–190 (2007).
  • Underhill DM. Collaboration between the innate immune receptors dectin-1, TLRs and Nods. Immunol. Rev.219, 75–87 (2007).
  • Re F, Strominger JL. IL-10 released by concomitant TLR stimulation blocks the induction of a subset of Th1 cytokines that are specifically induced by TLR4 or TLR3 in human dendritic cells. J. Immunol.173, 7548–7555 (2004).
  • Chang J, Kunkel AL, Chang CH. Negative regulation of MyD88-dependent signalling by IL-10 in dendritic cells. Proc. Natl Acad. Sci. USA106, 18327–18332 (2009).
  • Fritz JH, Girardin SE, Fitting C et al. Synergistic stimulation of human monocytes and dendritic cells by Toll-like receptor 4 and NOD1- and NOD2-activating agonists. Eur. J. Immunol.35, 2459–2470 (2005).
  • Tada H, Aiba S, Shibata K, Ohteki T, Takada H. Synergistic effect of Nod1 and Nod2 agonists with Toll-like receptor agonists on human dendritic cells to generate interleukin-12 and T helper Type 1 cells. Infect. Immun.73, 7967–7976 (2005).
  • Wang J, Ma J, Charboneau R, Barke R, Roy S. Morphine inhibits murine dendritic cell IL-23 production by modulating Toll-like receptor 2 and Nod2 signaling. J. Biol. Chem.286, 10225–10232 (2011).
  • Dennehy KM, Ferwerda G, Faro-Trindade I et al. SYK kinase is required for collaborative cytokine production induced through Dectin-1 and Toll-like receptors. Eur. J. Immunol.38, 500–506 (2008).
  • Dan JM, Wang JP, Lee CK, Levitz SM. Cooperative stimulation of dendritic cells by Cryptococcus neoformans mannoproteins and CpG oligodeoxynucleotides. PLoS One3, e2046 (2008).
  • Holtick U, Klein-Gonzalez N, von Bergwelt-Baildon MS. Potential of Toll-like receptor 9 agonists in combined anticancer immunotherapy strategies: synergy of PAMPs and DAMPs? Immunotherapy3, 301–304 (2011).
  • Baba N, Samson S, Bourdet-Sicard R, Rubio M, Sarfati M. Selected commensal-related bacteria and Toll-like receptor 3 agonist combinatorial codes synergistically induce interleukin-12 production by dendritic cells to trigger a T helper Type 1 polarizing programme. Immunology128, e523–e531 (2009).
  • Montomoli E, Piccirella S, Khadang B, Mennitto E, Camerini R, De Rosa A. Current adjuvants and new perspectives in vaccine formulation. Expert Rev. Vaccines10(7), 1053–1061 (2011).
  • Seubert A, Calabro S, Santini L et al. Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88. Proc. Natl Acad. Sci. USA108, 11169–11174 (2011).
  • Franchi L, Nunez G. The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1β secretion but dispensable for adjuvant activity. Eur. J. Immunol.38, 2085–2089 (2008).
  • Flach TL, Ng G, Hari A et al. Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity. Nat. Med.17, 479–487 (2011).
  • Marichal T, Ohata K, Bedoret D et al. DNA released from dying host cells mediates aluminum adjuvant activity. Nat. Med.17, 996–1002 (2011).
  • O’Hagan DT, Rappuoli R, De Gregorio E, Tsai T, Del Giudice G. MF59 adjuvant: the best insurance against influenza strain diversity. Expert Rev. Vaccines10(4), 447–462 (2011).
  • Gilca V, De Serres G, Hamelin ME et al. Antibody persistence and response to 2010–2011 trivalent influenza vaccine one year after a single dose of 2009 AS03-adjuvanted pandemic H1N1 vaccine in children. Vaccine30(1), 35–41 (2011).
  • Herzog C, Hartmann K, Künzi V et al. Eleven years of Inflexal V-a virosomal adjuvanted influenza vaccine. Vaccine27, 4381–4387 (2009).
  • MacLeod MKL, McKee AS, David A et al. Vaccine adjuvants aluminum and monophosphoryl lipid A provide distinct signals to generate protective cytotoxic memory CD8 T cells. Proc. Natl Acad. Sci. USA108, 7914–7919 (2011).
  • Garçon N, Van Mechelen M. Recent clinical experience with vaccines using MPL- and QS-21-containing adjuvant systems. Expert Rev. Vaccines10(4), 471–486 (2011).
  • Didierlaurent AM, Morel S, Lockman L et al. AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J. Immunol.183, 6186–6197 (2009).
  • Brewer JM. (How) do aluminium adjuvants work? Immunol. Lett.102, 10–15 (2006).
  • Casella CR, Mitchell TC. Putting endotoxin to work for us: monophosphoryl lipid A as a safe and effective vaccine adjuvant. Cell. Mol. Life Sci.65, 3231–3240 (2008).
  • Cekic C, Casella CR, Eaves CA, Matsuzawa A, Ichijo H, Mitchell TC. Selective activation of the p38 MAPK pathway by synthetic monophosphoryl lipid A. J. Biol. Chem.284, 31982–31991 (2009).
  • Embry CA, Franchi L, Nuñez G, Mitchell TC. Mechanism of impaired NLRP3 inflammasome priming by monophosphoryl lipid A. Sci. Signal.4, ra28 (2011).
  • Duthie MS, Windish HP, Fox CB, Reed SG. Use of defined TLR ligands as adjuvants within human vaccines. Immunol. Rev.239, 178–196 (2011).
  • Tomai MA, Vasilakos JP. TLR-7 and -8 agonists as vaccine adjuvants. Expert. Rev. Vaccines10(4), 405–407 (2011).
  • Ellis RD, Martin LB, Shaffer D et al. Phase 1 trial of the Plasmodium falciparum blood stage vaccine MSP1(42)-C1/Alhydrogel with and without CPG 7909 in malaria naive adults. PLoS One5, e8787 (2010).
  • Duncan CJ, Sheehy SH, Ewer KJ et al. Impact on malaria parasite multiplication rates in infected volunteers of the protein-in-adjuvant vaccine AMA1-C1/Alhydrogel+CPG 7909. PLoS One6, e22271 (2011).
  • Ichinohe T, Ainai A, Tashiro M, Sata T, Hasegawa H. Poly I: polyC12U adjuvant-combined intranasal vaccine protects mice against highly pathogenic H5N1 influenza virus variants. Vaccine27, 6276–6279 (2009).
  • Mizel SB, Bates JT. Flagellin as an adjuvant: cellular mechanisms and potential. J. Immunol.185, 5677–5682 (2010).
  • Querec T, Bennouna S, Alkan S et al. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity. J. Exp. Med.203, 413–424 (2006).
  • Olafsdottir TA, Lingnau K, Nagy E, Jonsdottir I. Novel protein-based pneumococcal vaccines administered with the Th1-promoting adjuvant IC31 induce protective immunity against pneumococcal disease in neonatal mice. Infect. Immun.80(1), 461–468 (2012).
  • Bernardo L, Pavón A, Hermida L et al. The two component adjuvant IC31® potentiates the protective immunity induced by a dengue 2 recombinant fusion protein in mice. Vaccine29, 4256–4263 (2011).
  • van Dissel JT, Soonawala D, Joosten SA et al. Ag85B-ESAT-6 adjuvanted with IC31® promotes strong and long-lived Mycobacterium tuberculosis specific T cell responses in volunteers with previous BCG vaccination or tuberculosis infection. Vaccine29, 2100–2109 (2011).
  • Henriksen-Lacey M, Devitt A, Perrie Y. The vesicle size of DDA. TDB liposomal adjuvants plays a role in the cell-mediated immune response but has no significant effect on antibody production. J. Cont. Release154, 131–137 (2011).
  • Fomsgaard A, Karlsson I, Gram G et al. Development and preclinical safety evaluation of a new therapeutic HIV-1 vaccine based on 18 T-cell minimal epitope peptides applying a novel cationic adjuvant CAF01. Vaccine29, 7067–7074 (2011).
  • Wilson NS, Yang B, Morelli AB et al. ISCOMATRIX vaccines mediate CD8+ T-cell cross-priming by a MyD88-dependent signaling pathway. Immunol. Cell Biol. doi:10.1038/icb.2011.71 (2011) (Epub ahead of print).
  • Agrawal S, Agrawal A, Doughty B et al. Cutting edge: different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos. J. Immunol.171, 4984–4989 (2003).
  • Agrawal A, Dillon S, Denning TL, Pulendran B. ERK1-/- mice exhibit Th1 cell polarization and increased susceptibility to experimental autoimmune encephalomyelitis. J. Immunol.176, 5788–5796 (2006).
  • Yanagawa Y, Onoe K. Enhanced IL-10 production by TLR4- and TLR2-primed dendritic cells upon TLR restimulation. J. Immunol.178, 6173–6180 (2007).
  • Jarnicki AG, Conroy H, Brereton C et al. Attenuating regulatory T cell induction by TLR agonists through inhibition of p38 MAPK signaling in dendritic cells enhances their efficacy as vaccine adjuvants and cancer immunotherapeutics. J. Immunol.180, 3797–3806 (2008).
  • Redecke V, Hacker H, Datta SK et al. Cutting Edge: activation of Toll-like receptor 2 Induces a Th2 immune response and promotes experimental asthma. J. Immunol.172, 2739–2743 (2004).
  • Mitchell D, Yong M, Raju J et al. Toll-like receptor-mediated adjuvanticity and immunomodulation in dendritic cells: implications for peptide vaccines. Hum. Vaccines (Suppl. 7), 85–93 (2011).
  • Fritz JH, Le Bourhis L, Sellge G et al. Nod1-mediated innate immune recognition of peptidoglycan contributes to the onset of adaptive immunity. Immunity26, 445–459 (2007).
  • Dowling D, Hamilton CM, O’Neill SM. A comparative analysis of cytokine responses, cell surface marker expression and MAPKs in DCs matured with LPS compared with a panel of TLR ligands. Cytokine41, 254–262 (2008).
  • Dearman RJ, Cumberbatch M, Maxwell G, Basketter DA, Kimber I. Toll-like receptor ligand activation of murine bone marrow-derived dendritic cells. Immunology126, 475–484 (2008).
  • Kawasaki T, Kawai T, Akira S. Recognition of nucleic acids by pattern-recognition receptors and its relevance in autoimmunity. Immunol. Rev.243, 61–73 (2011).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.