Community Research and Development Information Service - CORDIS

FP7

TLR4-CAT Result In Brief

Project ID: 326481
Funded under: FP7-PEOPLE
Country: United Kingdom

A new vaccine adjuvant

Vaccine design often entails the use of adjuvant formulations that enhance protective cellular immune responses. European researchers worked on the mode of action of a newly synthesised lipid as a vaccine adjuvant.
A new vaccine adjuvant
Adjuvants get recognised by toll-like receptors (TLRs) and trigger a state of emergency, rendering the vaccine more efficient. Understanding TLR-mediated signalling is therefore a prerequisite to rational adjuvant design for vaccines.

Bacterial lipopolysaccharides (LPS), are major components of the outer membrane of Gram-negative bacteria, and are recognised by TLR4. Most synthetic adjuvants that mimic LPS structure have proven to be toxic, necessitating new, safer adjuvants.

Scientists on the EU-funded TLR4-CAT (A new class of cationic lipids that activate innate immune receptors) project studied the newly synthesised cationic lipid diC14-amidine for its capacity to serve as a vaccine adjuvant. DiC14-amidine activates TLR4, inducing pro-inflammatory cytokine secretion in immune cells and is easy to synthesise. In particular, scientists were interested to elucidate the structural basis of the interaction between diC14-amidine and TLR4.

In this context, TLR4-CAT took advantage of the species-dependent activity of TLR4 and diC14-amidine, and generated chimeric constructs made from human and horse protein. This allowed them to identify two distinct regions in the human TLR4 that modulate the agonist activity of diC14-amidine.

Through a series of competition and docking assays, scientists verified that diC14-amidine interacted with TLR4 via a mechanism different to that proposed previously for LPS and its derivatives. Interestingly, the subsequent cell signalling activated by diC14-amidine mimicked that of nickel ions. Further characterisation of the signalling activated by diC14-amidine, showed that it did not require the presence of the co-receptor CD14 to function.

Taken together, TLR4-CAT activities provided significant molecular insight into the interaction of diC14-amidine and TLR4 at the structural level. Although initially designed as a transfection agent, the generated evidence indicated that diC14-amidine has the potential to serve as an efficient vaccine adjuvant.

Related information

Keywords

Vaccine, adjuvant, LPS, diC14-amidine, TLR4, CD14
Record Number: 188319 / Last updated on: 2016-08-19
Domain: Biology, Medicine