Molecular characterisation of Toll-like receptor 4 biased signalling through the TIR-domain-containing adapter-inducing interferon-beta

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Development of successful vaccination strategies in humans of all ages is important not only for healthy ageing across the lifecourse, but also to reduce antimicrobial resistance. Vaccination of animals both to prevent animal diseases and to reduce the burden of zoonotic pathogens is critical to improve animal health and welfare as well as increasing food security. Adjuvants are molecules used to to improve the efficiency of vaccines in man and animals. Many adjuvants target a class of receptors that recognise pathogenic micro-organisms called Pattern Recognition Receptors (PRRs). One PRR, Toll-like Receptor 4 (TLR4), is important for recognising Gram negative bacteria and protecting the host against infections with these bacterial species. Over activity of this receptor, however, leads to severe inflammation and it is thought that increased activation of TLR4 as we age underpins many of the conditions commonly seen in an ageing population. TLR4 activates separate, but linked arms of the immune response. One arm, through a protein called Toll-Interleukin 1 Receptor (TIR)-domain-containing adapter-inducing interferon-beta (Trif), is very efficient at facilitating the development of protective vaccine responses. The other, through a protein called Myeloid Differentiation Primary Response 88 (MyD88), protects animals against Gram negative bacterial infections. An adjuvant molecule monophosphoryl lipid A (MPLA) selectively activates Trif in humans, but the mechanisms by which this occurs are not understood. In this grant we will determine how MPLA activates TLR4-Trif by changing the structure of TLR4 and determining whether this alters activation of Trif and/or MyD88. We will also determine the protein complexes formed by Trif after MPLA activation of immune cells. Finally we will try and identify molecules that will selectively target TLR4 and Trif driven immune responses to generate new compounds for vaccine adjuvants and other therapeutic applications.