Relationship between Structures and Biological Activities of Mycoplasmal Diacylated Lipopeptides and Their Recognition by Toll-Like Receptors 2 and 6

Okusawa, Tsugumi; Fujita, Mari; Nakamura, Jun Ichiro; Into, Takeshi; Yasuda, Motoaki; Yoshimura, Atsutoshi; Hara, Yoshitaka; Hasebe, Akira; Golenbock, Douglas T.; Morita, Manabu; Kuroki, Yoshio; Ogawa, Tomohiko; Shibata, Ken Ichiro

doi:10.1128/iai.72.3.1657-1665.2004

Cited by 159 publications

(167 citation statements)

References 42 publications

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“…[85][86][87][88] In contradistinction to Gram-negative LPS which is recognized by TLR4, 21,32-37 the lipopeptides signal via TLR2. 77,85,87,89 Although diacyl lipopeptides have been reported to be agonists of heterodimers of TLR2/ TLR6, 86,90,91 and triacylated species were thought to signal via TLR2/TLR1, 77,87,89 the recognition of the lipopeptides by TLR2 has been recently shown to be relatively independent of TLR1 and TLR6, and are mediated predominantly via TLR2. 92,93 Structural basis for the interactions of PAM 2 CSK 4 with TLR2 and PAM 3 CSK 4 with TLR2/TLR1.…”

Section: Tlr4 Agonists-lipopolysaccharide Monophosphoryl Lipid a Andmentioning

confidence: 99%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

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Section: Tlr4 Agonists-lipopolysaccharide Monophosphoryl Lipid a Andmentioning

confidence: 99%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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“…Natural TLR2 ligands of bacterial origin, such as MALP-2 (31,41,42) and FSL-1, (32) have been reported to effectively activate CD8-positive T cells and induce antitumor activity. Because these lipopeptides are hydrophilic, it was predicted that the hydrophilicity of the peptide might be important for its activity.…”

Section: Discussionmentioning

confidence: 99%

“…(32) Bacterial and synthetic TLR2 ligands (MALP-2, FSL-1, (32) ) contain mostly hydrophilic peptides, and the presence of solubilizers critically affects their TLR2 agonistic ability, (34) suggesting that the activity of compounds as TLR2 agonists correlates with their solubility.…”

Section: Interleukin (Il)-23 and Interferon (Ifn)-c Are The Main Cytomentioning

confidence: 99%

“…The N-terminal cysteine of the 13-amino-acid peptide of bacterial origin was modified with 2 palmitates [Pam2Cys or P2C, S-(2,3-bispalmitoyloxypropyl)-cysteine], (31) but P2C alone does not work as a TLR2 ligand. (32) Bacterial and synthetic TLR2 ligands (MALP-2, FSL-1, (32) P2C-SKKKK (33) ) contain mostly hydrophilic peptides, and the presence of solubilizers critically affects their TLR2 agonistic ability, (34) suggesting that the activity of compounds as TLR2 agonists correlates with their solubility.…”

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confidence: 99%

“…No functional consensus peptide sequences were identified in MALP-2. The N-terminal cysteine of the 13-amino-acid peptide of bacterial origin was modified with 2 palmitates [Pam2Cys or P2C, S-(2,3-bispalmitoyloxypropyl)-cysteine], (31) but P2C alone does not work as a TLR2 ligand.(32) Bacterial and synthetic TLR2 ligands (MALP-2, FSL-1, (32) ) contain mostly hydrophilic peptides, and the presence of solubilizers critically affects their TLR2 agonistic ability, (34) suggesting that the activity of compounds as TLR2 agonists correlates with their solubility.CD11c is a member of the integrin superfamily and is known to be a marker of DCs.(35) Dendritic cells also express other integrin molecules such as aV ⁄ b3 and a5 ⁄ b1, and the RGDS motif specifically binds to these integrins. …”

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Adjuvant engineering for cancer immunotherapy: Development of a synthetic TLR2 ligand with increased cell adhesion

Akazawa

Inoue²,

Shime

et al. 2010

Cancer Science

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The development of effective immunoadjuvants for tumor immunotherapy is of fundamental importance. The use of Mycobacterium bovis bacillus Calmette-Gué rin cell wall skeleton (BCG-CWS) in tumor immunotherapy has been examined in various clinical applications. Because BCG-CWS is a macromolecule that cannot be chemically synthesized, the development of an alternative synthetic molecule is necessary to ensure a constant supply of adjuvant. In the present study, a new adjuvant was designed based on the structure of macrophage-activating lipopeptide (MALP)-2, which is a Toll-like receptor (TLR)-2 ligand similar to BCG-CWS. Macrophage-activating lipopeptide-2, [S-(2,3-bispalmitoyloxypropyl)Cys (P2C) -GNNDESNISFKEK], originally identified in a Mycoplasma species, is a lipopeptide that can be chemically synthesized. A MALP-2 peptide was substituted with a functional motif, RGDS, creating a novel molecule named P2C-RGDS. RGDS was selected because its sequence constitutes an integrin-binding motif and various integrins are expressed in immune cells including dendritic cells (DCs). Thus, this motif adds functionality to the ligand. P2C-RGDS activated DCs and splenocytes more efficiently than MALP-2 over short incubation times in vitro, and the RGDS motif contributed to their activation. Furthermore, P2C-RGDS showed higher activity than MALP-2 in inducing migration of DCs to draining lymph node, and in inhibiting tumor growth in vivo. This process of designing and developing synthetic adjuvants has been named ''adjuvant engineering,'' and the evaluation and improvement of P2C-RGDS constitutes a first step in the development of stronger synthetic adjuvants in the future. (Cancer Sci 2010; 101: 1596-1603 B acterial adjuvants that were used as biological response modifiers (BRM) for cancer immunotherapy in the 1970s have recently been re-evaluated.(1-3) Cancer antigens that had been identified in many laboratories were tested as peptide vaccines for clinical applications, but the peptides alone were not sufficient to fully activate the immune system.(4) These results suggested that the activation of the innate immune system, including dendritic cells (DCs), by a supporting adjuvant was important.(5-8) In peptide vaccine therapy, the T cells of the acquired immune system play an important role in recognizing and attacking tumor cells.(9) Dendritic cells play a key role in the regulation of the acquired immune system by presenting antigen and inducing a primary immune response. The identification of the Toll-like receptor (TLR) family advanced the understanding of DC function and of the role of adjuvants, because almost all microbial adjuvants work as TLR ligands and activate DCs.(10-12) These findings provide the basis for the understanding of the mechanism of adjuvant therapy.Dr Azuma developed BCG-CWS, a cell-wall skeleton preparation of Mycobacterium bovis bacillus Calmette-Guérin, (13,14) as an antitumor immunotherapeutic adjuvant. Although many BRM studies have been discontinued, basic and clinical research on BCG-CWS has...

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A common human TLR1 polymorphism regulates the innate immune response to lipopeptides

et al. 2007

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Toll-like receptors (TLR) are critical mediators of the immune response to pathogens and human polymorphisms in this gene family regulate inflammatory pathways and are associated with susceptibility to infection. Lipopeptides are present in a wide variety of microbes and stimulate immune responses through TLR1/2 or TLR2/6 heterodimers. It is not currently known whether polymorphisms in TLR1 regulate the innate immune response. We stimulated human whole blood with triacylated lipopeptide, a ligand for TLR1/2 heterodimers, and found substantial inter-individual variation in the immune response. We sequenced the coding region of TLR1 and found a non-synonymous polymorphism, I602S (base pair T1805G), that regulated signalling. In comparison to TLR1_602S, the 602I variant mediated substantially greater basal and lipopeptide-induced NF-kappaB signalling in transfected HEK293 cells. These signalling differences among TLR1 variants were also found with stimulation by extracts of Mycobacterium tuberculosis. Furthermore, individuals with the 602II genotype produced substantially more IL-6 than those with the 602SS variant in a lipopeptide-stimulated whole-blood cytokine assay. Together, these observations demonstrate that variation in the inflammatory response to bacterial lipopeptides is regulated by a common TLR1 transmembrane domain polymorphism that could potentially impact the innate immune response and clinical susceptibility to a wide spectrum of pathogens.

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Relationship between Structures and Biological Activities of Mycoplasmal Diacylated Lipopeptides and Their Recognition by Toll-Like Receptors 2 and 6

Cited by 159 publications

References 42 publications

Potential adjuvantic properties of innate immune stimuli

Potential adjuvantic properties of innate immune stimuli

Adjuvant engineering for cancer immunotherapy: Development of a synthetic TLR2 ligand with increased cell adhesion

A common human TLR1 polymorphism regulates the innate immune response to lipopeptides

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