484
Views
17
CrossRef citations to date
0
Altmetric
Review

Advances in Antiviral Therapies Targeting Toll-like Receptors

, , &
Pages 437-453 | Received 18 Nov 2015, Accepted 10 Feb 2016, Published online: 29 Feb 2016

References

  • Roach JC, Glusman G, Rowen L, et al. The evolution of vertebrate toll-like receptors. Proc Natl Acad Sci U S A. 2005;102:9577–9582.
  • Takeda K, Akira S, TLR signaling pathways. Semin Immunol. 2004;16:3–9.
  • Janeway CA Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol. 1989;54(Pt 1):1–13.
  • Lemaitre B, Nicolas E, Michaut L, et al. The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996;86:973–983.
  • Schenten D, Medzhitov R. The control of adaptive immune responses by the innate immune system. Adv Immunol. 2011;109:87–124.
  • Yesudhas D, Gosu V, Anwar MA, et al. Multiple roles of toll-like receptor 4 in colorectal cancer. Front Immunol. 2014;5:334.
  • Finlay BB, McFadden G. Anti-immunology: evasion of the host immune system by bacterial and viral pathogens. Cell. 2006;124:767–782.
  • Patel MC, Shirey KA, Pletneva LM, et al. Novel drugs targeting Toll-like receptors for antiviral therapy. Future Virol. 2014;9:811–829.
  • Akira S, Takeda K, Toll-like receptor signalling. Nat Rev Immunol. 2004;4:499–511.
  • Kumar H, Kawai T, Akira S. Toll-like receptors and innate immunity. Biochem Biophys Res Commun. 2009;388:621–625.
  • Zanoni I, Ostuni R, Marek LR, et al. CD14 controls the LPS-induced endocytosis of toll-like receptor 4. Cell. 2011;147:868–880.
  • Barton GM, Kagan JC. A cell biological view of toll-like receptor function: regulation through compartmentalization. Nat Rev Immunol. 2009;9:535–542.
  • Kurt-Jones EA, Popova L, Kwinn L, et al. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol. 2000;1:398–401.
  • Bowie A, Kiss-Toth E, Symons JA, et al. A46R and A52R from vaccinia virus are antagonists of host IL-1 and toll-like receptor signaling. Proc Natl Acad Sci U S A. 2000;97:10162–10167.
  • 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. 2007;292:H251–8.
  • Reinert LS, Harder L, Holm CK, et al. TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice. J Clin Invest. 2012;122:1368–1376.
  • Abe Y, Fujii K, Nagata N, et al. The toll-like receptor 3-mediated antiviral response is important for protection against poliovirus infection in poliovirus receptor transgenic mice. J Virol. 2012;86:185–194.
  • Daffis S, Samuel MA, Suthar MS, et al. Toll-like receptor 3 has a protective role against West Nile virus infection. J Virol. 2008;82:10349–10358.
  • Georgel P, Jiang Z, Kunz S, et al. Vesicular stomatitis virus glycoprotein G activates a specific antiviral toll-like receptor 4-dependent pathway. Virology. 2007;362:304–313.
  • Gowen BB, Hoopes JD, Wong M-H, et al. TLR3 deletion limits mortality and disease severity due to Phlebovirus infection. J Immunol. 2006;177:6301–6307.
  • Handke W, Oelschlegel R, Franke R, et al. Hantaan virus triggers TLR3-dependent innate immune responses. J Immunol. 2009;182:2849–2858.
  • Haynes LM, Moore DD, Kurt-Jones EA, et al. Involvement of toll-like receptor 4 in innate immunity to respiratory syncytial virus. J Virol. 2001;75:10730–10737.
  • Hutchens M, Luker KE, Sottile P, et al. TLR3 increases disease morbidity and mortality from vaccinia infection. J Immunol. 2008;180:483–491.
  • Le Goffic R, Balloy V, Lagranderie M, et al. Detrimental contribution of the toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog. 2006;2:e53.
  • Okumura A, Pitha PM, Yoshimura A, et al. Interaction between Ebola virus glycoprotein and host toll-like receptor 4 leads to induction of proinflammatory cytokines and SOCS1. J Virol. 2010;84:27–33.
  • Pott J, Stockinger S, Torow N, et al. Age-dependent TLR3 expression of the intestinal epithelium contributes to rotavirus susceptibility. PLoS Pathog. 2012;8:e1002670.
  • Rassa JC, Meyers JL, Zhang Y, et al. Murine retroviruses activate B cells via interaction with toll-like receptor 4. Proc Natl Acad Sci U S A. 2002;99:2281–2286.
  • Richer MJ, Lavallee DJ, Shanina I, et al. Toll-like receptor 3 signaling on macrophages is required for survival following coxsackievirus B4 infection. PLoS One. 2009;4:e4127.
  • Tsai Y-T, Chang S-Y, Lee C-N, et al. Human TLR3 recognizes dengue virus and modulates viral replication in vitro. Cell Microbiol. 2009;11:604–615.
  • Wang N, Liang Y, Devaraj S, et al. Toll-like receptor 3 mediates establishment of an antiviral state against hepatitis C virus in hepatoma cells. J Virol. 2009;83:9824–9834.
  • Wang T, Town T, Alexopoulou L, et al. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med. 2004;10:1366–1373.
  • Davidson S, Kaiko G, Loh Z, et al. Plasmacytoid dendritic cells promote host defense against acute pneumovirus infection via the TLR7-MyD88-dependent signaling pathway. J Immunol. 2011;186:5938–5948.
  • 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. Immunity. 2004;21:107–119.
  • Lund J, Sato A, Akira S, et al. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med. 2003;198:513–520.
  • Meier A, Chang JJ, Chan ES, et al. Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1. Nat Med. 2009;15:955–959.
  • Samuelsson C, Hausmann J, Lauterbach H, et al. Survival of lethal poxvirus infection in mice depends on TLR9, and therapeutic vaccination provides protection. J Clin Invest. 2008;118:1776–1784.
  • Town T, Bai F, Wang T, et al. Toll-like receptor 7 mitigates lethal West Nile encephalitis via interleukin 23-dependent immune cell infiltration and homing. Immunity. 2009;30:242–253.
  • Gitlin L, Barchet W, Gilfillan S, et al. Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc Natl Acad Sci U S A. 2006;103:8459–8464.
  • Heil F, Hemmi H, Hochrein H, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004;303:1526–1529.
  • Hornung V, Ellegast J, Kim S, et al. 5’-Triphosphate RNA is the ligand for RIG-I. Science. 2006;314:994–997.
  • Iwakiri D, Zhou L, Samanta M, et al. Epstein-Barr virus (EBV)-encoded small RNA is released from EBV-infected cells and activates signaling from Toll-like receptor 3. J Exp Med. 2009;206:2091–2099.
  • Kato H, Takeuchi O, Sato S, et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 2006;441:101–105.
  • Martinelli E, Cicala C, Van Ryk D, et al. HIV-1 gp120 inhibits TLR9-mediated activation and IFN-{alpha} secretion in plasmacytoid dendritic cells. Proc Natl Acad Sci U S A. 2007;104:3396–3401.
  • Perlman S, Netland J. Coronaviruses post-SARS: update on replication and pathogenesis. Nat Rev Microbiol. 2009;7:439–450.
  • Pichlmair A, Schulz O, Tan CP, et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5’-phosphates. Science. 2006;314:997–1001.
  • Samanta M, Iwakiri D, Kanda T, et al. EB virus-encoded RNAs are recognized by RIG-I and activate signaling to induce type I IFN. Embo J. 2006;25:4207–4214.
  • Ariza M-E, Glaser R, Kaumaya PT, et al. The EBV-encoded dUTPase activates NF-kappa B through the TLR2 and MyD88-dependent signaling pathway. J Immunol. 2009;182:851–859.
  • Compton T, Kurt-Jones EA, Boehme KW, et al. Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2. J Virol. 2003;77:4588–4596.
  • Dolganiuc A, Oak S, Kodys K, et al. Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation. Gastroenterology. 2004;127:1513–1524.
  • Ge Y, Mansell A, Ussher JE, et al. Rotavirus NSP4 triggers secretion of proinflammatory cytokines from macrophages via toll-like receptor 2. J Virol. 2013;87:11160–11167.
  • Leoni V, Gianni T, Salvioli S, et al. Herpes simplex virus glycoproteins gH/gL and gB bind toll-like receptor 2, and soluble gH/gL is sufficient to activate NF-κB. J Virol. 2012;86:6555–6562.
  • Murawski MR, Bowen GN, Cerny AM, et al. Respiratory syncytial virus activates innate immunity through toll-like receptor 2. J Virol. 2009;83:1492–1500.
  • Sorensen LN, Reinert LS, Malmgaard L, et al. TLR2 and TLR9 synergistically control herpes simplex virus infection in the brain. J Immunol. 2008;181:8604–8612.
  • Bieback K, Lien E, Klagge IM, et al. Hemagglutinin protein of wild-type measles virus activates toll-like receptor 2 signaling. J Virol. 2002;76:8729–8736.
  • Thompson MR, Kaminski JJ, Kurt-Jones EA, et al. Pattern recognition receptors and the innate immune response to viral infection. Viruses. 2011;3:920–940.
  • Carty M, Bowie AG. Recent insights into the role of toll-like receptors in viral infection. Clin Exp Immunol. 2010;161:397–406.
  • Welte T, Reagan K, Fang H, et al. Toll-like receptor 7-induced immune response to cutaneous West Nile virus infection. J Gen Virol. 2009;90:2660–2668.
  • Trinchieri G, Sher A. Cooperation of toll-like receptor signals in innate immune defence. Nat Rev Immunol. 2007;7:179–190.
  • Bowie AG, Unterholzner L, Viral evasion and subversion of pattern-recognition receptor signalling. Nat Rev Immunol. 2008;8:911–922.
  • Lester SN, Li K. Toll-like receptors in antiviral innate immunity. J Mol Biol. 2014;426:1246–1264.
  • Abe T, Kaname Y, Hamamoto I, et al. Hepatitis C virus nonstructural protein 5A modulates the toll-like receptor-MyD88-dependent signaling pathway in macrophage cell lines. J Virol. 2007;81:8953–8966.
  • Bauhofer O, Summerfield A, Sakoda Y, et al. Classical swine fever virus Npro interacts with interferon regulatory factor 3 and induces its proteasomal degradation. J Virol. 2007;81:3087–3096.
  • Cardenas WB, Loo YM, Gale M Jr., et al. Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling. J Virol. 2006;80:5168–5178.
  • Chen Z, Rijnbrand R, Jangra RK, et al. Ubiquitination and proteasomal degradation of interferon regulatory factor-3 induced by Npro from a cytopathic bovine viral diarrhea virus. Virology. 2007;366:277–292.
  • Hatada E, Fukuda R. Binding of influenza A virus NS1 protein to dsRNA in vitro. J Gen Virol. 1992;73(Pt 12):3325–3329.
  • Lang T, Lo C, Skinner N, et al. The hepatitis B e antigen (HBeAg) targets and suppresses activation of the toll-like receptor signaling pathway. J Hepatol. 2011;55:762–769.
  • Lei X, Sun Z, Liu X, et al. Cleavage of the adaptor protein TRIF by enterovirus 71 3C inhibits antiviral responses mediated by toll-like receptor 3. J Virol. 2011;85:8811–8818.
  • Lei X, Xiao X, Xue Q, et al. Cleavage of interferon regulatory factor 7 by enterovirus 71 3C suppresses cellular responses. J Virol. 2013;87:1690–1698.
  • Li K, Foy E, Ferreon JC, et al. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the toll-like receptor 3 adaptor protein TRIF. Proc Natl Acad Sci U S A. 2005;102:2992–2997.
  • Melroe GT, Silva L, Schaffer PA, et al. Recruitment of activated IRF-3 and CBP/p300 to herpes simplex virus ICP0 nuclear foci: potential role in blocking IFN-beta induction. Virology. 2007;360:305–321.
  • Qu L, Feng Z, Yamane D, et al. Disruption of TLR3 signaling due to cleavage of TRIF by the hepatitis a virus protease-polymerase processing intermediate, 3CD. PLoS Pathog. 2011;7:e1002169.
  • Shah M, Anwar MA, Park S, et al. In silico mechanistic analysis of IRF3 inactivation and high-risk HPV E6 species-dependent drug response. Sci Rep. 2015;5:13446.
  • Van Lint AL, Murawski MR, Goodbody RE, et al. Herpes simplex virus immediate-early ICP0 protein inhibits toll-like receptor 2-dependent inflammatory responses and NF-kappaB signaling. J Virol. 2010;84:10802–10811.
  • Wang D, Fang L, Li K, et al. Foot-and-mouth disease virus 3C protease cleaves NEMO to impair innate immune signaling. J Virol. 2012;86:9311–9322.
  • Wang H, Ryu WS. Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3: implications for immune evasion. PLoS Pathog. 2010;6:e1000986.
  • Abdul-Careem MF, Firoz Mian M, Gillgrass AE, et al. FimH, a TLR4 ligand, induces innate antiviral responses in the lung leading to protection against lethal influenza infection in mice. Antiviral Res. 2011;92:346–355.
  • Ahmad H, Gubbels R, Ehlers E, et al. Kaposi sarcoma-associated herpesvirus degrades cellular toll-interleukin-1 receptor domain-containing adaptor-inducing beta-interferon (TRIF). J Biol Chem. 2011;286:7865–7872.
  • Bahar MW, Graham SC, Chen RA, et al. How vaccinia virus has evolved to subvert the host immune response. J Struct Biol. 2011;175:127–134.
  • Benfield CT, Ren H, Lucas SJ, et al. Vaccinia virus protein K7 is a virulence factor that alters the acute immune response to infection. J Gen Virol. 2013;94:1647–1657.
  • Devaraj SG, Wang N, Chen Z, et al. Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus. J Biol Chem. 2007;282:32208–32221.
  • Fang X, Gao J, Zheng H, et al. The membrane protein of SARS-CoV suppresses NF-kappaB activation. J Med Virol. 2007;79:1431–1439.
  • Harte MT, Haga IR, Maloney G, et al. The poxvirus protein A52R targets toll-like receptor signaling complexes to suppress host defense. J Exp Med. 2003;197:343–351.
  • Lee HR, Kim MH, Lee JS, et al. Viral interferon regulatory factors. J Interferon Cytokine Res. 2009;29:621–627.
  • Lu LL, Puri M, Horvath CM, et al. Select paramyxoviral V proteins inhibit IRF3 activation by acting as alternative substrates for inhibitor of kappaB kinase epsilon (IKKe)/TBK1. J Biol Chem. 2008;283:14269–14276.
  • Mansur DS, Maluquer De Motes C, Unterholzner L, et al. Poxvirus targeting of E3 ligase beta-TrCP by molecular mimicry: a mechanism to inhibit NF-kappaB activation and promote immune evasion and virulence. PLoS Pathog. 2013;9:e1003183.
  • Mielech AM, Kilianski A, Baez-Santos YM, et al. MERS-CoV papain-like protease has deISGylating and deubiquitinating activities. Virology. 2014;450-451:64–70.
  • Niemeyer D, Zillinger T, Muth D, et al. Middle East respiratory syndrome coronavirus accessory protein 4a is a type I interferon antagonist. J Virol. 2013;87:12489–12495.
  • Okumura A, Alce T, Lubyova B, et al. HIV-1 accessory proteins VPR and Vif modulate antiviral response by targeting IRF-3 for degradation. Virology. 2008;373:85–97.
  • Pfaller CK, Conzelmann -K-K. Measles virus V protein is a decoy substrate for IkappaB kinase alpha and prevents Toll-like receptor 7/9-mediated interferon induction. J Virol. 2008;82:12365–12373.
  • Ren J, Liu T, Pang L, et al. A novel mechanism for the inhibition of interferon regulatory factor-3-dependent gene expression by human respiratory syncytial virus NS1 protein. J Gen Virol. 2011;92:2153–2159.
  • Stack J, Haga IR, Schroder M, et al. Vaccinia virus protein A46R targets multiple toll-like-interleukin-1 receptor adaptors and contributes to virulence. J Exp Med. 2005;201:1007–1018.
  • Sun L, Xing Y, Chen X, et al. Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. PLoS One. 2012;7:e30802.
  • Weeks KM, Ampe C, Schultz SC, et al. Fragments of the HIV-1 Tat protein specifically bind TAR RNA. Science. 1990;249:1281–1285.
  • Yang Y, Zhang L, Geng H, et al. The structural and accessory proteins M, ORF 4a, ORF 4b, and ORF 5 of Middle East respiratory syndrome coronavirus (MERS-CoV) are potent interferon antagonists. Protein Cell. 2013;4:951–961.
  • Chua BY, Zeng W, Lau YF, et al. Comparison of lipopeptide-based immunocontraceptive vaccines containing different lipid groups. Vaccine. 2007;25:92–101.
  • Borsutzky S, Kretschmer K, Becker PD, et al. The mucosal adjuvant macrophage-activating lipopeptide-2 directly stimulates B lymphocytes via the TLR2 without the need of accessory cells. J Immunol. 2005;174:6308–6313.
  • Hochrein H, Schlatter B, O’Keeffe M, et al. Herpes simplex virus type-1 induces IFN-alpha production via toll-like receptor 9-dependent and -independent pathways. Proc Natl Acad Sci U S A. 2004;101:11416–11421.
  • Zhu J, Huang X, Yang Y. Innate immune response to adenoviral vectors is mediated by both toll-like receptor-dependent and -independent pathways. J Virol. 2007;81:3170–3180.
  • Troutman TD, Hu W, Fulenchek S, et al. Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt. Proc Natl Acad Sci U S A. 2012;109:273–278.
  • Rose WA 2nd, McGowin CL, Pyles RB. FSL-1, a bacterial-derived toll-like receptor 2/6 agonist, enhances resistance to experimental HSV-2 infection. Virol J. 2009;6:195.
  • Tan AC, Mifsud EJ, Zeng W, et al. Intranasal administration of the TLR2 agonist Pam2Cys provides rapid protection against influenza in mice. Mol Pharm. 2012;9:2710–2718.
  • Cheng K, Gao M, Godfroy JI, et al. Specific activation of the TLR1-TLR2 heterodimer by small-molecule agonists. Sci Adv. 2015;1:e1400139–e1400139.
  • Lau Y-F, Tang L-H, Ooi -E-E. A TLR3 ligand that exhibits potent inhibition of influenza virus replication and has strong adjuvant activity has the potential for dual applications in an influenza pandemic. Vaccine. 2009;27:1354–1364.
  • Cardoso EC, Pereira NZ, Mitsunari GE, et al. TLR7/TLR8 activation restores defective cytokine secretion by myeloid dendritic cells but not by plasmacytoid dendritic cells in HIV-infected pregnant women and newborns. PLoS One. 2013;8:e67036.
  • Tajuddin T, Ryan EJ, Norris S, et al. Interferon-α suppressed granulocyte colony stimulating factor production is reversed by CL097, a TLR7/8 agonist. J Gastroenterol Hepatol. 2010;25:1883–1890.
  • Reppe K, Radunzel P, Dietert K, et al. Pulmonary immunostimulation with MALP-2 in influenza virus-infected mice increased survival after pneumococcal superinfection. Infect Immun. 2015;83:4617–4629.
  • Vitiello A, Ishioka G, Grey HM, et al. Development of a lipopeptide-based therapeutic vaccine to treat chronic HBV infection. I. Induction of a primary cytotoxic T lymphocyte response in humans. J Clin Invest. 1995;95:341–349.
  • Durier C, Launay O, Meiffredy V, et al. Clinical safety of HIV lipopeptides used as vaccines in healthy volunteers and HIV-infected adults. Aids. 2006;20:1039–1049.
  • Goujard C, Marcellin F, Hendel-Chavez H, et al. Interruption of antiretroviral therapy initiated during primary HIV-1 infection: impact of a therapeutic vaccination strategy combined with interleukin (IL)-2 compared with IL-2 alone in the ANRS 095 randomized study. AIDS Res Hum Retroviruses. 2007;23:1105–1113.
  • Launay O, Durier C, Desaint C, et al. Cellular immune responses induced with dose-sparing intradermal administration of HIV vaccine to HIV-uninfected volunteers in the ANRS VAC16 trial. PLoS One. 2007;2(8):e725.
  • Ichinohe T, Kawaguchi A, Tamura S, et al. Intranasal immunization with H5N1 vaccine plus poly I:poly C12U, a toll-like receptor agonist, protects mice against homologous and heterologous virus challenge. Microbes Infect. 2007;9:1333–1340.
  • Fujimoto C, Nakagawa Y, Ohara K, et al. Polyriboinosinic polyribocytidylic acid [poly(I:C)]/TLR3 signaling allows class I processing of exogenous protein and induction of HIV-specific CD8+ cytotoxic T lymphocytes. Int Immunol. 2004;16:55–63.
  • Trumpfheller C, Caskey M, Nchinda G, et al. The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine. Proc Natl Acad Sci U S A. 2008;105:2574–2579.
  • Gram GJ, Karlsson I, Agger EM, et al. A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice. PLoS One. 2009;4:e6950.
  • Nordly P, Rose F, Christensen D, et al. Immunity by formulation design: induction of high CD8+ T-cell responses by poly(I:C) incorporated into the CAF01 adjuvant via a double emulsion method. J Control Release. 2011;150:307–317.
  • Dupont J, Altclas J, Lepetic A, et al. A controlled clinical trial comparing the safety and immunogenicity of a new adjuvanted hepatitis B vaccine with a standard hepatitis B vaccine. Vaccine. 2006;24:7167–7174.
  • Bienzle U, Gunther M, Neuhaus R, et al. Immunization with an adjuvant hepatitis B vaccine after liver transplantation for hepatitis B-related disease. Hepatology. 2003;38:811–819.
  • Sokal EM, Hoppenbrouwers K, Vandermeulen C, et al. Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy young adults. J Infect Dis. 2007;196:1749–1753.
  • Xiong D, Song L, Zhai X, et al. A porcine reproductive and respiratory syndrome virus (PRRSV) vaccine candidate based on the fusion protein of PRRSV glycoprotein 5 and the toll-like receptor-5 agonist Salmonella Typhimurium FljB. BMC Vet Res. 2015;11:121.
  • Wille-Reece U, Flynn BJ, Lore K, et al. HIV Gag protein conjugated to a toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates. Proc Natl Acad Sci U S A. 2005;102:15190–15194.
  • Siegrist C-A, Pihlgren M, Tougne C, et al. Co-administration of CpG oligonucleotides enhances the late affinity maturation process of human anti-hepatitis B vaccine response. Vaccine. 2004;23:615–622.
  • Cooper CL, Davis HL, Morris ML, et al. Safety and immunogenicity of CPG 7909 injection as an adjuvant to Fluarix influenza vaccine. Vaccine. 2004;22:3136–3143.
  • Alexopoulou L, Holt AC, Medzhitov R, et al. Recognition of double-stranded RNA and activation of NF-kappaB by toll-like receptor 3. Nature. 2001;413:732–738.
  • Mazaleuskaya L, Veltrop R, Ikpeze N, et al. Protective role of Toll-like receptor 3-induced type I interferon in murine coronavirus infection of macrophages. Viruses. 2012;4:901–923.
  • Zhao J, Wohlford-Lenane C, Zhao J, et al. Intranasal treatment with poly(I•C) protects aged mice from lethal respiratory virus infections. J Virol. 2012;86:11416–11424.
  • 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. 2008;205:1601–1610.
  • Matsumoto M, Seya T. TLR3: interferon induction by double-stranded RNA including poly(I:C). Adv Drug Deliv Rev. 2008;60:805–812.
  • Wang Y, Cella M, Gilfillan S, et al. Cutting edge: polyinosinic:polycytidylic acid boosts the generation of memory CD8 T cells through melanoma differentiation-associated protein 5 expressed in stromal cells. J Immunol. 2010;184:2751–2755.
  • Gowen BB, Wong M-H, Jung K-H, et al. TLR3 is essential for the induction of protective immunity against Punta Toro virus infection by the double-stranded RNA (dsRNA), poly(I:C12U), but not poly(I:C): differential recognition of synthetic dsRNA molecules. J Immunol. 2007;178:5200–5208.
  • Wong JP, Christopher ME, Viswanathan S, et al. Antiviral role of toll-like receptor-3 agonists against seasonal and avian influenza viruses. Curr Pharm Des. 2009;15:1269–1274.
  • Boukhvalova MS, Sotomayor TB, Point RC, et al. Activation of interferon response through toll-like receptor 3 impacts viral pathogenesis and pulmonary toll-like receptor expression during respiratory syncytial virus and influenza infections in the cotton rat Sigmodon hispidus model. J Interferon Cytokine Res. 2010;30:229–242.
  • Caskey M, Lefebvre F, Filali-Mouhim A, et al. Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans. J Exp Med. 2011;208:2357–2366.
  • Shen E, Li L, Li L, et al. PIKA as an adjuvant enhances specific humoral and cellular immune responses following the vaccination of mice with HBsAg plus PIKA. Cell Mol Immunol. 2007;4:113–120.
  • Ismaili J, Rennesson J, Aksoy E, et al. Monophosphoryl lipid A activates both human dendritic cells and T cells. J Immunol. 2002;168:926–932.
  • Evans JT, Cluff CW, Johnson DA, et al. Enhancement of antigen-specific immunity via the TLR4 ligands MPL adjuvant and Ribi.529. Expert Rev Vaccines. 2003;2:219–229.
  • Petrovsky N, Aguilar JC. Vaccine adjuvants: current state and future trends. Immunol Cell Biol. 2004;82:488–496.
  • Qureshi N, Takayama K, Ribi E. Purification and structural determination of nontoxic lipid A obtained from the lipopolysaccharide of Salmonella typhimurium. J Biol Chem. 1982;257:11808–11815.
  • Rappuoli R, Mandl CW, Black S, et al. Vaccines for the twenty-first century society. Nat Rev Immunol. 2011;11:865–872.
  • Garcon N, Van Mechelen M. Recent clinical experience with vaccines using MPL- and QS-21-containing adjuvant systems. Expert Rev Vaccines. 2011;10:471–486.
  • Angelone DF, Wessels MR, Coughlin M, et al. Innate immunity of the human newborn is polarized toward a high ratio of IL-6/TNF-alpha production in vitro and in vivo. Pediatr Res. 2006;60:205–209.
  • Levy O, Zarember KA, Roy RM, et al. Selective impairment of TLR-mediated innate immunity in human newborns: neonatal blood plasma reduces monocyte TNF-alpha induction by bacterial lipopeptides, lipopolysaccharide, and imiquimod, but preserves the response to R-848. J Immunol. 2004;173:4627–4634.
  • Prince GA, Jenson AB, Hemming VG, et al. Enhancement of respiratory syncytial virus pulmonary pathology in cotton rats by prior intramuscular inoculation of formalin-inactiva ted virus. J Virol. 1986;57:721–728.
  • Prince GA, Curtis SJ, Yim KC, et al. Vaccine-enhanced respiratory syncytial virus disease in cotton rats following immunization with Lot 100 or a newly prepared reference vaccine. J Gen Virol. 2001;82:2881–2888.
  • Prince GA, Denamur F, Deschamps M, et al. Monophosphoryl lipid A adjuvant reverses a principal histologic parameter of formalin-inactivated respiratory syncytial virus vaccine-induced disease. Vaccine. 2001;19:2048–2054.
  • Boukhvalova MS, Prince GA, Soroush L, et al. The TLR4 agonist, monophosphoryl lipid A, attenuates the cytokine storm associated with respiratory syncytial virus vaccine-enhanced disease. Vaccine. 2006;24:5027–5035.
  • Kamphuis T, Shafique M, Meijerhof T, et al. Efficacy and safety of an intranasal virosomal respiratory syncytial virus vaccine adjuvanted with monophosphoryl lipid A in mice and cotton rats. Vaccine. 2013;31:2169–2176.
  • Blanco JC, Boukhvalova MS, Pletneva LM, et al. A recombinant anchorless respiratory syncytial virus (RSV) fusion (F) protein/monophosphoryl lipid A (MPL) vaccine protects against RSV-induced replication and lung pathology. Vaccine. 2014;32:1495–1500.
  • Schmidt AC, Johnson TR, Openshaw PJ, et al. Respiratory syncytial virus and other pneumoviruses: a review of the international symposium–RSV 2003. Virus Res. 2004;106:1–13.
  • Blanco JC, Boukhvalova MS, Shirey KA, et al. New insights for development of a safe and protective RSV vaccine. Hum Vaccin. 2010;6:482–492.
  • Taylor DN, Treanor JJ, Strout C, et al. Induction of a potent immune response in the elderly using the TLR-5 agonist, flagellin, with a recombinant hemagglutinin influenza-flagellin fusion vaccine (VAX125, STF2.HA1 SI). Vaccine. 2011;29:4897–4902.
  • Hossain MS, Ramachandiran S, Gewirtz AT, et al., . . Recombinant TLR5 agonist CBLB502 promotes NK cell-mediated anti-CMV immunity in mice. PLoS One. 2014;9(5):e96165.
  • Hemmi H, Kaisho T, Takeuchi O, et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol. 2002;3:196–200.
  • Gorden KB, Gorski KS, Gibson SJ, et al. Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol. 2005;174:1259–1268.
  • Miller RL, Meng T-C, Tomai MA. The antiviral activity of Toll-like receptor 7 and 7/8 agonists. Drug News Perspect. 2008;21:69–87.
  • Nian H, Geng WQ, Cui HL, et al. R-848 triggers the expression of TLR7/8 and suppresses HIV replication in monocytes. BMC Infect Dis. 2012;12:5.
  • Fidock MD, Souberbielle BE, Laxton C, et al. The innate immune response, clinical outcomes, and ex vivo HCV antiviral efficacy of a TLR7 agonist (PF-4878691). Clin Pharmacol Ther. 2011;89:821–829.
  • Jones HM, Chan PL, Van Der Graaf PH, et al. Use of modelling and simulation techniques to support decision making on the progression of PF-04878691, a TLR7 agonist being developed for hepatitis C. Br J Clin Pharmacol. 2012;73:77–92.
  • Xiang AX, Webber SE, Kerr BM, et al. Discovery of ANA975: an oral prodrug of the TLR-7 agonist isatoribine. Nucleosides Nucleotides Nucleic Acids. 2007;26:635–640.
  • Bergmann JF, De Bruijne J, Hotho DM, et al. Randomised clinical trial: anti-viral activity of ANA773, an oral inducer of endogenous interferons acting via TLR7, in chronic HCV. Aliment Pharmacol Ther. 2011;34:443–453.
  • Boonstra A, Liu B-S, Groothuismink ZM, et al. Potent immune activation in chronic hepatitis C patients upon administration of an oral inducer of endogenous interferons that acts via toll-like receptor 7. Antivir Ther. 2012;17:657–667.
  • Isobe Y, Kurimoto A, Tobe M, et al. Synthesis and biological evaluation of novel 9-substituted-8-hydroxyadenine derivatives as potent interferon inducers. J Med Chem. 2006;49:2088–2095.
  • Lanford RE, Guerra B, Chavez D, et al. GS-9620, an oral agonist of toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology. 2013;144:1508-17, 17 e1-10.
  • Lopatin U, Wolfgang G, Tumas D, et al. Safety, pharmacokinetics and pharmacodynamics of GS-9620, an oral toll-like receptor 7 agonist. Antivir Ther. 2013;18:409–418.
  • Steinhagen F, Kinjo T, Bode C, et al. TLR-based immune adjuvants. Vaccine. 2011;29:3341–3355.
  • Malaspina A, Moir S, DiPoto AC, et al. CpG oligonucleotides enhance proliferative and effector responses of B cells in HIV-infected individuals. J Immunol. 2008;181:1199–1206.
  • Vicari AP, Schmalbach T, Lekstrom-Himes J, et al. Safety, pharmacokinetics and immune effects in normal volunteers of CPG 10101 (ACTILON), an investigational synthetic toll-like receptor 9 agonist. Antivir Ther. 2007;12:741–751.
  • McHutchison JG, Bacon BR, Gordon SC, et al. Phase 1B, randomized, double-blind, dose-escalation trial of CPG 10101 in patients with chronic hepatitis C virus. Hepatology. 2007;46:1341–1349.
  • Kandimalla ER, Bhagat L, Zhu FG, et al. A dinucleotide motif in oligonucleotides shows potent immunomodulatory activity and overrides species-specific recognition observed with CpG motif. Proc Natl Acad Sci U S A. 2003;100:14303–14308.
  • Kandimalla ER, Bhagat L, Li Y, et al. Immunomodulatory oligonucleotides containing a cytosine-phosphate-2’-deoxy-7-deazaguanosine motif as potent toll-like receptor 9 agonists. Proc Natl Acad Sci U S A. 2005;102:6925–6930.
  • Cheng K, Wang X, Yin H. Small-molecule inhibitors of the TLR3/dsRNA complex. J Am Chem Soc. 2011;133:3764–3767.
  • Cheng K, Wang X, Zhang S, et al. Discovery of small-molecule inhibitors of the TLR1/TLR2 complex. Angew Chem Int Ed Engl. 2012;51:12246–12249.
  • Kandimalla ER, Bhagat L, Wang D, et al. Design, synthesis and biological evaluation of novel antagonist compounds of toll-like receptors 7, 8 and 9. Nucleic Acids Res. 2013;41:3947–3961.
  • Lamphier M, Zheng W, Latz E, et al. Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivo. Mol Pharmacol. 2014;85:429–440.
  • Li Y, Cao H, Wang N, et al. A novel antagonist of TLR9 blocking all classes of immunostimulatory CpG-ODNs. Vaccine. 2011;29:2193–2198.
  • Park S-J, Kang SH, Kang YK, et al. Inhibition of homodimerization of toll-like receptor 4 by 4-oxo-4-(2-oxo-oxazolidin-3-yl)-but-2-enoic acid ethyl ester. Int Immunopharmacol. 2011;11:19–22.
  • Ramani V, Madhusoodhanan R, Kosanke S, et al. A TLR4-interacting SPA4 peptide inhibits LPS-induced lung inflammation. Innate Immun. 2013;19:596–610.
  • Robbins M, Judge A, Liang L, et al. 2’-O-methyl-modified RNAs act as TLR7 antagonists. Mol Ther. 2007;15:1663–1669.
  • Sioud M. Development of TLR7/8 small RNA antagonists. Methods Mol Biol. 2010;629:387–394.
  • Sugiyama K, Muroi M, Tanamoto K. A novel TLR4-binding peptide that inhibits LPS-induced activation of NF-kappaB and in vivo toxicity. Eur J Pharmacol. 2008;594:152–156.
  • Yan L, Liang J, Yao C, et al. Pyrimidine triazole thioether derivatives as toll-like receptor 5 (TLR5)/Flagellin complex inhibitors. ChemMedChem. 2015. doi:10.1002/cmdc.201500471.
  • Zhou S, Cerny AM, Bowen G, et al. Discovery of a novel TLR2 signaling inhibitor with anti-viral activity. Antiviral Res. 2010;87:295–306.
  • Ranjith-Kumar CT, Duffy KE, Jordan JL, et al. Single-stranded oligonucleotides can inhibit cytokine production induced by human toll-like receptor 3. Mol Cell Biol. 2008;28:4507–4519.
  • Skold AE, Hasan M, Vargas L, et al. Single-stranded DNA oligonucleotides inhibit TLR3-mediated responses in human monocyte-derived dendritic cells and in vivo in cynomolgus macaques. Blood. 2012;120:768–777.
  • Mullarkey M, Rose JR, Bristol J, et al. Inhibition of endotoxin response by e5564, a novel toll-like receptor 4-directed endotoxin antagonist. J Pharmacol Exp Ther. 2003;304:1093–1102.
  • Opal SM, Laterre P-F, Francois B, et al. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. Jama. 2013;309:1154–1162.
  • Imai Y, Kuba K, Neely GG, et al. Identification of oxidative stress and toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell. 2008;133:235–249.
  • Nhu QM, Shirey K, Teijaro JR, et al. Novel signaling interactions between proteinase-activated receptor 2 and toll-like receptors in vitro and in vivo. Mucosal Immunol. 2010;3:29–39.
  • Schaal JB, Tran D, Tran P, et al., . . Rhesus macaque theta defensins suppress inflammatory cytokines and enhance survival in mouse models of bacteremic sepsis. PLoS One. 2012;7(12):e51337.
  • Lehrer RI, Cole AM, Selsted ME. θ-Defensins: cyclic peptides with endless potential. J Biol Chem. 2012;287:27014–27019.
  • Tang YQ, Yuan J, Osapay G, et al. A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated alpha-defensins. Science. 1999;286:498–502.
  • Kokryakov VN, Harwig SS, Panyutich EA, et al. Protegrins: leukocyte antimicrobial peptides that combine features of corticostatic defensins and tachyplesins. FEBS Lett. 1993;327:231–236.
  • Robinson RA, DeVita VT, Levy HB, et al. A phase I-II trial of multiple-dose polyriboinosic-polyribocytidylic acid in patieonts with leukemia or solid tumors. J Natl Cancer Inst. 1976;57:599–602.
  • Anwar MA, Basith S, Choi S. Negative regulatory approaches to the attenuation of toll-like receptor signaling. Exp Mol Med. 2013;45:e11.
  • Lavieri R, Piccioli P, Carta S, et al. TLR costimulation causes oxidative stress with unbalance of proinflammatory and anti-inflammatory cytokine production. J Immunol. 2014;192:5373–5381.
  • Tuvim MJ, Gilbert BE, Dickey BF, et al. Synergistic TLR2/6 and TLR9 activation protects mice against lethal influenza pneumonia. PLoS One. 2012;7(1):e30596.
  • Kwon JA, Rho HM. Hepatitis B viral core protein activates the hepatitis B viral enhancer II/pregenomic promoter through the nuclear factor kappaB binding site. Biochem Cell Biol. 2002;80:445–455.
  • Toussi DN, Massari P. Immune adjuvant effect of molecularly-defined toll-like receptor ligands. Vaccines (Basel). 2014;2:323–353.
  • Averett DR, Fletcher SP, Li W, et al. The pharmacology of endosomal TLR agonists in viral disease. Biochem Soc Trans. 2007;35:1468–1472.
  • Engel AL, Holt GE, Lu H. The pharmacokinetics of Toll-like receptor agonists and the impact on the immune system. Expert Rev Clin Pharmacol. 2011;4:275–289.

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.