A novel vaccine adjuvant comprised of a synthetic innate defence regulator peptide and CpG oligonucleotide links innate and adaptive immunity

Kindrachuk, Jason; Jenssen, Håvard; Elliott, Melissa; Townsend, Rebecca; Nijnik, Anastasia; Lee, Song F.; Gerdts, Volker; Babiuk, Lorne A.; Halperin, Scott A.; Hancock, Robert E. W.

doi:10.1016/j.vaccine.2009.05.094

Cited by 74 publications

(72 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6). This suggests that the protective activity of IDR-1002 was likely mediated through enhanced leukocyte recruitment to the site of infection rather than through direct effects of the peptide on the microbicidal activities of the recruited leukocytes; however, we cannot rule out that additional activities of IDR-1002 not detected in our studies may emerge in vivo as a result of synergy with the action of bacterial compounds or other host mediators, as exemplified by the synergy in the various immunomodulatory properties of natural and synthetic cationic peptides with IL-1b, GM-CSF, and CpG oligonucleotides (38,39,46,47).…”

Section: Effects Of Idr-1002 On Microbicidal Activities Of Leukocytesmentioning

confidence: 75%

Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

Nijnik

Madera

et al. 2010

The Journal of Immunology

Self Cite

182

225

View full text Add to dashboard Cite

With the rapid rise in the incidence of multidrug resistant infections, there is substantial interest in host defense peptides as templates for production of new antimicrobial therapeutics. Natural peptides are multifunctional mediators of the innate immune response, with some direct antimicrobial activity and diverse immunomodulatory properties. We have previously developed an innate defense regulator (IDR) 1, with protective activity against bacterial infection mediated entirely through its effects on the immunity of the host, as a novel approach to anti-infective therapy. In this study, an immunomodulatory peptide IDR-1002 was selected from a library of bactenecin derivatives based on its substantially more potent ability to induce chemokines in human PBMCs. The enhanced chemokine induction activity of the peptide in vitro correlated with stronger protective activity in vivo in the Staphylococcus aureus-invasive infection model, with a >5-fold reduction in the protective dose in direct comparison with IDR-1. IDR-1002 also afforded protection against the Gram-negative bacterial pathogen Escherichia coli. Chemokine induction by IDR-1002 was found to be mediated through a Gi-coupled receptor and the PI3K, NF-κB, and MAPK signaling pathways. The protective activity of the peptide was associated with in vivo augmentation of chemokine production and recruitment of neutrophils and monocytes to the site of infection. These results highlight the importance of the chemokine induction activity of host defense peptides and demonstrate that the optimization of the ex vivo chemokine-induction properties of peptides is a promising method for the rational development of immunomodulatory IDR peptides with enhanced anti-infective activity.

show abstract

Section: Effects Of Idr-1002 On Microbicidal Activities Of Leukocytesmentioning

confidence: 75%

Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

Nijnik

Madera

et al. 2010

The Journal of Immunology

Self Cite

182

225

View full text Add to dashboard Cite

show abstract

“…This sequence shares the same ancestor as the other sequences used in this study, it has relatively improved activity, and it has been employed previously as an adjuvant (15,16). We replaced two or three amino acids to produce new peptides the peptide, and the first column gives the amino acid species.…”

Section: Resultsmentioning

confidence: 99%

In Vitro and In Vivo Activities of Antimicrobial Peptides Developed Using an Amino Acid-Based Activity Prediction Method

Wang

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

cTo design and discover new antimicrobial peptides (AMPs) with high levels of antimicrobial activity, a number of machinelearning methods and prediction methods have been developed. Here, we present a new prediction method that can identify novel AMPs that are highly similar in sequence to known peptides but offer improved antimicrobial activity along with lower host cytotoxicity. Using previously generated AMP amino acid substitution data, we developed an amino acid activity contribution matrix that contained an activity contribution value for each amino acid in each position of the model peptide. A series of AMPs were designed with this method. After evaluating the antimicrobial activities of these novel AMPs against both Gram-positive and Gram-negative bacterial strains, DP7 was chosen for further analysis. Compared to the parent peptide HH2, this novel AMP showed broad-spectrum, improved antimicrobial activity, and in a cytotoxicity assay it showed lower toxicity against human cells. The in vivo antimicrobial activity of DP7 was tested in a Staphylococcus aureus infection murine model. When inoculated and treated via intraperitoneal injection, DP7 reduced the bacterial load in the peritoneal lavage solution. Electron microscope imaging and the results indicated disruption of the S. aureus outer membrane by DP7. Our new prediction method can therefore be employed to identify AMPs possessing minor amino acid differences with improved antimicrobial activities, potentially increasing the therapeutic agents available to combat multidrug-resistant infections.A ntimicrobial peptides (AMPs) are produced by multicellular organisms to defend against microbial infections. Along with potent antimicrobial activity, many AMPs also have the ability to enhance immunity by functioning as immunomodulators (1-3). AMPs therefore have excellent therapeutic potential, especially in light of increased drug resistance to many conventional antibiotic therapies. A number of naturally occurring peptides and synthetic derivatives have been developed or are currently in development (2, 4-6). Although AMPs vary in length, amino acid composition, and structure, they share some similarities, such as electrical charge and amphipathicity (3, 7). To determine the characteristics that are important in antimicrobial activity, bioinformatic tools and prediction methods have been developed (8), all based to some extent on the sequence similarities between peptides (9-11).To optimize the antimicrobial activity of identified AMPs and to predict novel peptide sequences, we present a machine-learning method based on the concept of an antimicrobial activity contribution score for each amino acid. Here, we consider that each amino acid in a peptide sequence possesses a different level of importance for the biological activity of that peptide, and this is represented by an assigned score. By calculation of each amino acid's contribution score, we can predict the antimicrobial activity of an AMP.To verify our results, we tested some of our designed AMPs ...

show abstract

“…In fact, HDP-based peptides have been shown to enhance vaccination efficiency in several in vivo models, in which the vaccination mixture contains synthetic DNA (43)(44)(45)(46)(47). Although little is known about the effects of these specific HDPs on DNA-induced immune activation, it is possible that part of their efficacy comes from increasing the proinflammatory DNA-induced immune response.…”

Section: Discussionmentioning

confidence: 99%

Importance of Endosomal Cathelicidin Degradation To Enhance DNA-Induced Chicken Macrophage Activation

Coorens

Dijk

Bikker

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Cathelicidins are essential in the protection against invading pathogens through both their direct antimicrobial activity and their immunomodulatory functions. Although cathelicidins are known to modulate activation by several TLR ligands, little is known about their influence on DNA-induced macrophage activation. In this study, we explored the effects of cathelicidins on DNA-induced activation of chicken macrophages and elucidated the intracellular processes underlying these effects. Our results show that chicken cathelicidin (CATH)-2 strongly enhances DNA-induced activation of both chicken and mammalian macrophages because of enhanced endocytosis of DNA–CATH-2 complexes. After endocytosis, DNA is liberated from the complex because of proteolytic breakdown of CATH-2, after which TLR21 is activated. This leads to increased cytokine expression and NO production. Through the interaction with DNA, CATH-2 can play an important role in modulating the immune response at sites of infection. These observations underline the importance of cathelicidins in sensing bacterial products and regulating immune responses.

show abstract

A novel vaccine adjuvant comprised of a synthetic innate defence regulator peptide and CpG oligonucleotide links innate and adaptive immunity

Cited by 74 publications

References 46 publications

Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

In Vitro and In Vivo Activities of Antimicrobial Peptides Developed Using an Amino Acid-Based Activity Prediction Method

Importance of Endosomal Cathelicidin Degradation To Enhance DNA-Induced Chicken Macrophage Activation

Contact Info

Product

Resources

About