Modulating immunity as a therapy for bacterial infections (original) (raw)

• Clark, I. A. The advent of the cytokine storm. Immunol. Cell Biol. 85, 271–273 (2007).
  Article CAS PubMed Google Scholar
• Ulevitch, R. J. Therapeutics targeting the innate immune system. Nature Rev. Immunol. 4, 512–520 (2004).
  Article CAS Google Scholar
• Hamill, P., Brown, K., Jenssen, H. & Hancock, R. E. Novel anti-infectives: is host defence the answer? Curr. Opin. Biotechnol. 19, 628–636 (2008).
  Article CAS PubMed Google Scholar
• Yang, Y. F. et al. Long-term efficacy of interferon α therapy on hepatitis B viral replication in patients with chronic hepatitis B: a meta-analysis. Antiviral Res. 85, 361–365 (2010).
  Article CAS PubMed Google Scholar
• Jiang, X. R. et al. Advances in the assessment and control of the effector functions of therapeutic antibodies. Nature Rev. Drug Discov. 10, 101–111 (2011).
  Article CAS Google Scholar
• Scherer, A. & McLean, A. Mathematical models of vaccination. Br. Med. Bull. 62, 187–199 (2002).
  Article PubMed Google Scholar
• Karin, M., Lawrence, T. & Nizet, V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 124, 823–835 (2006).
  Article CAS PubMed Google Scholar
• Zasloff, M. Antimicrobial peptides of multicellular organisms. Nature 415, 389–395 (2002).
  Article CAS PubMed Google Scholar
• Fjell, C. D., Hiss, J. A., Hancock, R. E. W. & Schneider, G. Designing antimicrobial peptides: form follows function. Nature Rev Drug Discov 11, 37–51 (2011).
  Article CAS Google Scholar
• Trinchieri, G. & Sher, A. Cooperation of Toll-like receptor signals in innate immune defence. Nature Rev. Immunol. 7, 179–190 (2007).
  Article CAS Google Scholar
• Medzhitov, R., Preston-Hurlburt, P. & Janeway, C. A. Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397 (1997).
  Article CAS PubMed Google Scholar
• Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).
  Article CAS PubMed Google Scholar
• Ferwerda, B. et al. Functional consequences of Toll-like receptor 4 polymorphisms. Mol. Med. 14, 346–352 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Hennessy, E. J., Parker, A. E. & O'Neill, L. A. Targeting Toll-like receptors: emerging therapeutics? Nature Rev. Drug Discov. 9, 293–307 (2010). A highly comprehensive review of the ongoing development of TLR agonists and antagonists for therapeutic applications.
  Article CAS Google Scholar
• Zaheer, S. A. et al. Combined multidrug and Mycobacterium w vaccine therapy in patients with multibacillary leprosy. J. Infect. Dis. 167, 401–410 (1993).
  Article CAS PubMed Google Scholar
• Klinman, D. M., Xie, H. & Ivins, B. E. CpG oligonucleotides improve the protective immune response induced by the licensed anthrax vaccine. Ann. NY Acad. Sci. 1082, 137–150 (2006).
  Article CAS PubMed Google Scholar
• Pastorelli, L., Pizarro, T. T., Cominelli, F. & Vecchi, M. Emerging drugs for the treatment of ulcerative colitis. Expert Opin. Emerg. Drugs 14, 505–521 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Rozy, A. & Chorostowska-Wynimko, J. Bacterial immunostimulants — mechanism of action and clinical application in respiratory diseases. Pneumonol. Alergol. Pol. 76, 353–359 (2008).
  PubMed Google Scholar
• Ruah, S. B., Ruah, C., van Aubel, A., Abel, S. & Elsasser, U. Efficacy of a polyvalent bacterial lysate in children with recurrent respiratory tract infections. Adv. Ther. 18, 151–162 (2001).
  Article CAS PubMed Google Scholar
• Dittmer, U. & Olbrich, A. R. Treatment of infectious diseases with immunostimulatory oligodeoxynucleotides containing CpG motifs. Curr. Opin. Microbiol. 6, 472–477 (2003).
  Article CAS PubMed Google Scholar
• Evans, S. E. et al. Stimulated innate resistance of lung epithelium protects mice broadly against bacteria and fungi. Am. J. Respir. Cell Mol. Biol. 42, 40–50 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Munoz, N. et al. Mucosal administration of flagellin protects mice from Streptococcus pneumoniae lung infection. Infect. Immun. 78, 4226–4233 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Yu, F. S. et al. Flagellin stimulates protective lung mucosal immunity: role of cathelicidin-related antimicrobial peptide. J. Immunol. 185, 1142–1149 (2010).
  Article CAS PubMed Google Scholar
• Kinnebrew, M. A. et al. Bacterial flagellin stimulates Toll-like receptor 5-dependent defense against vancomycin-resistant Enterococcus infection. J. Infect. Dis. 201, 534–543 (2010).
  Article CAS PubMed Google Scholar
• Clement, C. G. et al. Stimulation of lung innate immunity protects against lethal pneumococcal pneumonia in mice. Am. J. Respir. Crit. Care Med. 177, 1322–1330 (2008).
  Article PubMed PubMed Central Google Scholar
• Ireland, R. et al. Effective, broad spectrum control of virulent bacterial infections using cationic DNA liposome complexes combined with bacterial antigens. PLoS Pathog. 6, e1000921 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Tuvim, M. J., Evans, S. E., Clement, C. G., Dickey, B. F. & Gilbert, B. E. Augmented lung inflammation protects against influenza A pneumonia. PLoS ONE 4, e4176 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Shinya, K. et al. Toll-like receptor pre-stimulation protects mice against lethal infection with highly pathogenic influenza viruses. Virol. J. 8, 97 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Antonelli, L. R. et al. Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population. J. Clin. Invest. 120, 1674–1682 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Hotchkiss, R. S. & Karl, I. E. The pathophysiology and treatment of sepsis. N. Engl. J. Med. 348, 138–150 (2003). An overview of the complex immune-mediated pathophysiology of sepsis and the complexities of treating patients with sepsis using immunomodulatory therapies.
  Article CAS PubMed Google Scholar
• Rice, T. W. et al. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit. Care Med. 38, 1685–1694 (2010).
  Article CAS PubMed Google Scholar
• Tidswell, M. et al. Phase 2 trial of eritoran tetrasodium (E5564), a Toll-like receptor 4 antagonist, in patients with severe sepsis. Crit. Care Med. 38, 72–83 (2010).
  Article CAS PubMed Google Scholar
• Barochia, A., Solomon, S., Cui, X., Natanson, C. & Eichacker, P. Q. Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies. Expert Opin. Drug Metab. Toxicol. 7, 479–494 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Ungaro, R. et al. A novel Toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1167–G1179 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004).
  Article CAS PubMed Google Scholar
• Abreu, M. T. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nature Rev. Immunol. 10, 131–144 (2010).
  Article CAS Google Scholar
• Dupaul-Chicoine, J. et al. Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity 32, 367–378 (2010).
  Article CAS PubMed Google Scholar
• Zaph, C. et al. Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis. Nature 446, 552–556 (2007).
  Article CAS PubMed Google Scholar
• Werts, C., Rubino, S., Ling, A., Girardin, S. E. & Philpott, D. J. Nod-like receptors in intestinal homeostasis, inflammation, and cancer. J. Leukoc. Biol. 90, 471–482 (2011).
  Article CAS PubMed Google Scholar
• Sorbara, M. & Philpott, D. Peptidoglycan: a critical activator of the mammalian immune system during infection and homeostasis. Immunol. Rev. 243, 40–60 (2011). A review of how peptidoglycan recognition shapes the mammalian immune response.
  Article CAS PubMed Google Scholar
• Leemans, J. C., Cassel, S. L. & Sutterwala, F. S. Sensing damage by the NLRP3 inflammasome. Immunol. Rev. 243, 152–162 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Spreafico, R., Ricciardi-Castagnoli, P. & Mortellaro, A. The controversial relationship between NLRP3, alum, danger signals and the next-generation adjuvants. Eur. J. Immunol. 40, 638–642 (2010).
  Article CAS PubMed Google Scholar
• Girardin, S. E. et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J. Biol. Chem. 278, 8869–8872 (2003).
  Article CAS PubMed Google Scholar
• Inohara, N. et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J. Biol. Chem. 278, 5509–5512 (2003).
  Article CAS PubMed Google Scholar
• Chedid, L., Audibert, F. & Johnson, A. G. Biological activities of muramyl dipeptide, a synthetic glycopeptide analogous to bacterial immunoregulating agents. Prog. Allergy 25, 63–105 (1978).
  CAS PubMed Google Scholar
• Fritz, J. H., et al. Nod1-mediated innate immune recognition of peptidoglycan contributes to the onset of adaptive immunity. Immunity 26, 445–459 (2007).
  Article CAS PubMed Google Scholar
• Magalhaes, J. G. et al. Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation. Proc. Natl Acad. Sci. USA 108, 14896–14901 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• O'Hagan, D. T. & De Gregorio, E. The path to a successful vaccine adjuvant – 'the long and winding road'. Drug Discov. Today 14, 541–551 (2009).
  Article CAS PubMed Google Scholar
• Bahr, G. M. Non-specific immunotherapy of HIV-1 infection: potential use of the synthetic immunodulator murabutide. J. Antimicrob. Chemother. 51, 5–8 (2003).
  Article CAS PubMed Google Scholar
• Mine, Y. et al. Immunoactive peptides, FK-156 and FK-565. I. Enhancement of host resistance to microbial infection in mice. J. Antibiot. (Tokyo) 36, 1045–1050 (1983).
  Article CAS Google Scholar
• Wardowska, A. et al. Analogues of muramyl dipeptide (MDP) and tuftsin limit infection and inflammation in murine model of sepsis. Vaccine 27, 369–374 (2009).
  Article CAS PubMed Google Scholar
• Geddes, K., Magalhaes, J. G. & Girardin, S. E. Unleashing the therapeutic potential of NOD-like receptors. Nature Rev. Drug Discov. 8, 465–479 (2009).
  Article CAS Google Scholar
• Fukushima, A. et al. Effect of MDP-Lys(L18) as a mucosal immunoadjuvant on protection of mucosal infections by Sendai virus and rotavirus. Vaccine 14, 485–491 (1996).
  Article CAS PubMed Google Scholar
• Sarkar, K. & Das, P. K. Protective effect of neoglycoprotein-conjugated muramyl dipeptide against Leishmania donovani infection: the role of cytokines. J. Immunol. 158, 5357–5365 (1997).
  CAS PubMed Google Scholar
• Le Bourhis, L. et al. Role of Nod1 in mucosal dendritic cells during Salmonella pathogenicity island 1-independent Salmonella enterica serovar Typhimurium infection. Infect. Immun. 77, 4480–4486 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• O'Reilly, T. & Zak, O. Enhancement of the effectiveness of antimicrobial therapy by muramyl peptide immunomodulators. Clin. Infect. Dis. 14, 1100–1109 (1992).
  Article CAS PubMed Google Scholar
• Kim, Y. G. et al. Viral infection augments Nod1/2 signaling to potentiate lethality associated with secondary bacterial infections. Cell Host Microbe 9, 496–507 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Argast, G. M., Fausto, N. & Campbell, J. S. Inhibition of RIP2/RICK/CARDIAK activity by pyridinyl imidazole inhibitors of p38 MAPK. Mol. Cell. Biochem. 268, 129–140 (2005).
  Article CAS PubMed Google Scholar
• Hancock, R. E. & Sahl, H. G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nature Biotech. 24, 1551–1557 (2006).
  Article CAS Google Scholar
• Nizet, V. et al. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 414, 454–457 (2001).
  Article CAS PubMed Google Scholar
• Ong, P. Y. et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N. Engl. J. Med. 347, 1151–1160 (2002).
  Article CAS PubMed Google Scholar
• Nijnik, A., Pistolic, J., Wyatt, A., Tam, S. & Hancock, R. E. Human cathelicidin peptide LL-37 modulates the effects of IFN-γ on APCs. J. Immunol. 183, 5788–5798 (2009).
  Article CAS PubMed Google Scholar
• Scott, M. G. et al. An anti-infective peptide that selectively modulates the innate immune response. Nature Biotech. 25, 465–472 (2007). A study demonstrating that a synthetic immunomodulatory peptide with no direct antimicrobial activity can offer protection against antibiotic-resistant infections in mouse models, while inhibiting an excessive inflammatory response.
  Article CAS Google Scholar
• Overhage, J. et al. The human host defence peptide LL-37 prevents bacterial biofilm formation. Infect Immun. 76, 4176–4182 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Carretero, M. et al. In vitro and in vivo wound healing-promoting activities of human cathelicidin LL-37. J. Invest. Dermatol. 128, 223–236 (2008).
  Article CAS PubMed Google Scholar
• Hirsch, T. et al. Human beta-defensin-3 promotes wound healing in infected diabetic wounds. J. Gene Med. 11, 220–228 (2009).
  Article CAS PubMed Google Scholar
• Easton, D. M., Nijnik, A., Mayer, M. L. & Hancock, R. E. Potential of immunomodulatory host defense peptides as novel anti-infectives. Trends Biotechnol. 27, 582–590 (2009). A recent comprehensive review of the ongoing development of synthetic peptides as immunomodulatory therapeutics.
  Article CAS PubMed PubMed Central Google Scholar
• Karaolis, D. K. et al. 3′,5′-cyclic diguanylic acid (c-di-GMP) inhibits basal and growth factor-stimulated human colon cancer cell proliferation. Biochem. Biophys. Res. Commun. 329, 40–45 (2005).
  Article CAS PubMed Google Scholar
• Brouillette, E., Hyodo, M., Hayakawa, Y., Karaolis, D. K. & Malouin, F. 3′,5′-cyclic diguanylic acid reduces the virulence of biofilm-forming Staphylococcus aureus strains in a mouse model of mastitis infection. Antimicrob. Agents Chemother. 49, 3109–3113 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Karaolis, D. K. et al. Bacterial c-di-GMP is an immunostimulatory molecule. J. Immunol. 178, 2171–2181 (2007).
  Article CAS PubMed Google Scholar
• Chen, W., Kuolee, R. & Yan, H. The potential of 3′,5′-cyclic diguanylic acid (c-di-GMP) as an effective vaccine adjuvant. Vaccine 28, 3080–3085 (2010).
  Article CAS PubMed Google Scholar
• Ebensen, T. et al. Bis-(3′,5′)-cyclic dimeric adenosine monophosphate: strong Th1/Th2/Th17 promoting mucosal adjuvant. Vaccine 29, 5210–5220 (2011).
  Article CAS PubMed Google Scholar
• Burdette, D. L. et al. STING is a direct innate immune sensor of cyclic di-GMP. Nature 478, 515–518 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Sauer, J. D. et al. The _N_-ethyl-_N_-nitrosourea-induced Goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides. Infect. Immun. 79, 688–694 (2011).
  Article CAS PubMed Google Scholar
• Woodward, J. J., Iavarone, A. T. & Portnoy, D. A. c-di-AMP secreted by intracellular Listeria monocytogenes activates a host type I interferon response. Science 328, 1703–1705 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Camilli, A. & Bassler, B. L. Bacterial small-molecule signaling pathways. Science 311, 1113–1116 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Smith, R. S., Harris, S. G., Phipps, R. & Iglewski, B. The Pseudomonas aeruginosa quorum-sensing molecule _N_-(3-oxododecanoyl)homoserine lactone contributes to virulence and induces inflammation in vivo. J. Bacteriol. 184, 1132–1139 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Teplitski, M., Mathesius, U. & Rumbaugh, K. P. Perception and degradation of _N_-acyl homoserine lactone quorum sensing signals by mammalian and plant cells. Chem. Rev. 111, 100–116 (2011). A thorough overview of the mechanisms of 'cross-kingdom' communication by quorum sensing molecules.
  Article CAS PubMed Google Scholar
• Mayer, M. L., Sheridan, J. A., Blohmke, C. J., Turvey, S. E. & Hancock, R. E. The Pseudomonas aeruginosa autoinducer 3O-C12 homoserine lactone provokes hyperinflammatory responses from cystic fibrosis airway epithelial cells. PLoS ONE 6, e16246 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Khajanchi, B. K., Kirtley, M. L., Brackman, S. M. & Chopra, A. K. Immunomodulatory and protective roles of quorum-sensing signaling molecules _N_-acyl homoserine lactones during infection of mice with Aeromonas hydrophila. Infect. Immun. 79, 2646–2657 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Mattmann, M. E. & Blackwell, H. E. Small molecules that modulate quorum sensing and control virulence in Pseudomonas aeruginosa. J. Org. Chem. 75, 6737–6746 (2010). A discussion about the strategies that can be used to interfere with quorum sensing pathways in Pseudomonas aeruginosa to potentially affect therapies.
  Article CAS PubMed PubMed Central Google Scholar
• Miyairi, S. et al. Immunization with 3-oxododecanoyl-L-homoserine lactone-protein conjugate protects mice from lethal Pseudomonas aeruginosa lung infection. J. Med. Microbiol. 55, 1381–1387 (2006).
  Article CAS PubMed Google Scholar
• Wu, H. et al. Synthetic furanones inhibit quorum-sensing and enhance bacterial clearance in Pseudomonas aeruginosa lung infection in mice. J. Antimicrob. Chemother. 53, 1054–1061 (2004).
  Article CAS PubMed Google Scholar
• Smyth, A. R. et al. Garlic as an inhibitor of Pseudomonas aeruginosa quorum sensing in cystic fibrosis—a pilot randomized controlled trial. Pediatr. Pulmonol. 45, 356–362 (2010).
  PubMed Google Scholar
• Brackman, G., Cos, P., Maes, L., Nelis, H. J. & Coenye, T. Quorum sensing inhibitors increase the susceptibility of bacterial biofilms to antibiotics in vitro and in vivo. Antimicrob. Agents Chemother. 55, 2655–2661 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Gardy, J. L., Lynn, D. J., Brinkman, F. S. & Hancock, R. E. Enabling a systems biology approach to immunology: focus on innate immunity. Trends Immunol. 30, 249–262 (2009). A review of the applications of bioinformatics and systems biology in the study of innate immunity and host–pathogen interactions, including many references to online resources, such as databases and software tools, that are openly available to the scientific community.
  Article CAS PubMed Google Scholar
• Park, B. S. et al. The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex. Nature 458, 1191–1195 (2009).
  Article CAS PubMed Google Scholar
• Jin, M. S. et al. Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 130, 1071–1082 (2007).
  Article CAS PubMed Google Scholar
• Choe, J., Kelker, M. S. & Wilson, I. A. Crystal structure of human Toll-like receptor 3 (TLR3) ectodomain. Science 309, 581–585 (2005).
  Article CAS PubMed Google Scholar
• Gavin, A. L. et al. Adjuvant-enhanced antibody responses in the absence of Toll-like receptor signaling. Science 314, 1936–1938 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Kasturi, S. P. et al. Programming the magnitude and persistence of antibody responses with innate immunity. Nature 470, 543–547 (2011). A recent study demonstrating that ligation of multiple TLRs by vaccine adjuvants is required for induction of long-term antibody responses and immunological memory.
  Article CAS PubMed PubMed Central Google Scholar
• Guy, B. The perfect mix: recent progress in adjuvant research. Nature Rev. Microbiol. 5, 505–517 (2007).
  CAS Google Scholar
• Biswas, S. K. & Lopez-Collazo, E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 30, 475–487 (2009).
  Article CAS PubMed Google Scholar
• Schellack, C. et al. IC31, a novel adjuvant signaling via TLR9, induces potent cellular and humoral immune responses. Vaccine 24, 5461–5472 (2006).
  Article CAS PubMed Google Scholar
• van Dissel, J. T. 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. Vaccine 29, 2100–2109 (2011).
  Article CAS PubMed Google Scholar
• Hilpert, K., Volkmer-Engert, R., Walter, T. & Hancock, R. E. High-throughput generation of small antibacterial peptides with improved activity. Nature Biotech. 23, 1008–1012 (2005).
  Article CAS Google Scholar
• Jenssen, H., Fjell, C. D., Cherkasov, A. & Hancock, R. E. QSAR modeling and computer-aided design of antimicrobial peptides. J. Pept. Sci. 14, 110–114 (2008).
  Article CAS PubMed Google Scholar
• Loose, C., Jensen, K., Rigoutsos, I. & Stephanopoulos, G. A linguistic model for the rational design of antimicrobial peptides. Nature 443, 867–869 (2006).
  Article CAS PubMed Google Scholar
• Braff, M. H. et al. Structure-function relationships among human cathelicidin peptides: dissociation of antimicrobial properties from host immunostimulatory activities. J. Immunol. 174, 4271–4278 (2005).
  Article CAS PubMed Google Scholar
• Nijnik, A. et al. Synthetic cationic peptide IDR-1002 provides protection against bacterial infections through chemokine induction and enhanced leukocyte recruitment. J. Immunol. 184, 2539–2550 (2010).
  Article CAS PubMed Google Scholar
• Fischer, P. M. The design, synthesis and application of stereochemical and directional peptide isomers: a critical review. Curr. Protein Pept. Sci. 4, 339–356 (2003).
  Article CAS PubMed Google Scholar
• Lande, R. et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449, 564–569 (2007).
  Article CAS PubMed Google Scholar
• Kindrachuk, J. et al. A novel vaccine adjuvant comprised of a synthetic innate defence regulator peptide and CpG oligonucleotide links innate and adaptive immunity. Vaccine 27, 4662–4671 (2009).
  Article CAS PubMed Google Scholar
• Martineau, A. R. et al. High-dose vitamin D3 during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial. Lancet 377, 242–250 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, P. T. et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311, 1770–1773 (2006). A study linking vitamin D deficiency to impaired immune defences against tuberculosis in the human population.
  Article CAS PubMed Google Scholar
• Raqib, R. et al. Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic. Proc. Natl Acad. Sci. USA 103, 9178–9183 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature 449, 819–826 (2007).
  Article CAS PubMed Google Scholar
• Kumar, H., Kawai, T. & Akira, S. Pathogen recognition by the innate immune system. Int. Rev. Immunol. 30, 16–34 (2009).
  Article CAS Google Scholar
• Lambrecht, B. N., Kool, M., Willart, M. A. & Hammad, H. Mechanism of action of clinically approved adjuvants. Curr. Opin. Immunol. 21, 23–29 (2009).
  Article CAS PubMed Google Scholar
• Nicholls, E. F., Madera, L. & Hancock, R. E. Immunomodulators as adjuvants for vaccines and antimicrobial therapy. Ann. NY Acad. Sci. 1213, 46–61 (2011).
  Article CAS Google Scholar
• Round, J. L. & Mazmanian, S. K. The gut microbiota shapes intestinal immune responses during health and disease. Nature Rev. Immunol. 9, 313–323 (2009).
  Article CAS Google Scholar
• Willing, B. P., Russell, S. L. & Finlay, B. B. Shifting the balance: antibiotic effects on host–microbiota mutualism. Nature Rev. Microbiol. 9, 233–243 (2011).
  Article CAS Google Scholar
• Lebeer, S., Vanderleyden, J. & De Keersmaecker, S. C. Host interactions of probiotic bacterial surface molecules: comparison with commensals and pathogens. Nature Rev. Microbiol. 8, 171–184 (2010). Three reviews (references 111–113) that cover the recent developments in our understanding of the host interactions with the gut microbiota and the roles of these interactions in health and disease.
  Article CAS Google Scholar
• Schlee, M. et al. Probiotic lactobacilli and VSL#3 induce enterocyte β-defensin 2. Clin. Exp. Immunol. 151, 528–535 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Schlee, M. et al. Induction of human β-defensin 2 by the probiotic Escherichia coli Nissle 1917 is mediated through flagellin. Infect. Immun. 75, 2399–2407 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Cosseau, C. et al. The commensal Streptococcus salivarius K12 downregulates the innate immune responses of human epithelial cells and promotes host-microbe homeostasis. Infect. Immun. 76, 4163–4175 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Hafez, M. et al. The K5 capsule of Escherichia coli strain Nissle 1917 is important in mediating interactions with intestinal epithelial cells and chemokine induction. Infect. Immun. 77, 2995–3003 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Senok, A. C., Verstraelen, H., Temmerman, M. & Botta, G. A. Probiotics for the treatment of bacterial vaginosis. Cochrane Database Syst. Rev. 4, CD006289 (2009).
  Google Scholar
• Twetman, S. & Stecksen-Blicks, C. Probiotics and oral health effects in children. Int. J. Paediatr. Dent. 18, 3–10 (2008).
  PubMed Google Scholar
• Wells, J. M. & Mercenier, A. Mucosal delivery of therapeutic and prophylactic molecules using lactic acid bacteria. Nature Rev. Microbiol. 6, 349–362 (2008).
  Article CAS Google Scholar
• Gaspari, A., Tyring, S. K. & Rosen, T. Beyond a decade of 5% imiquimod topical therapy. J. Drugs Dermatol. 8, 467–474 (2009). A recent summary of the applications of the TLR7 agonist imiquimod, one of the most widely used TLR agonists in the clinic.
  Google Scholar
• Harper, D. M. et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 367, 1247–1255 (2006). A report detailing the successful clinical trials of a human papilloma virus vaccine that uses an adjuvant formulation, including the TLR4 agonist MPL.
  Article CAS PubMed Google Scholar
• Dubensky, T. W. Jr & Reed, S. G. Adjuvants for cancer vaccines. Semin. Immunol. 22, 155–161 (2010).
  Article CAS PubMed Google Scholar