Determining the Molecular Mechanism of Covalently Linked TLR Agonists

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 DESCRIPTION (provided by applicant): Many viral vaccines stimulate the immune system through a synergistic combination of pattern recognition receptors. These combinations of agonists are critical for long-lived antibody and T- cell responses. These multi-agonist responses could be applied as new adjuvants, but the pathways and mechanisms through which they operate remain unclear. Our goal is to elucidate a mechanistic pathway for adjuvant synergies resulting from the molecular activation of two receptors by two covalently linked Toll-like Receptor (TLR) agonists (Dual_TLRs) on antigen presenting cells. We will determine the location of a set of synergies and the mechanism by which they occur. We will test the safety and efficacy of our synergistic adjuvants using model vaccines. We will use a combination of synthetic chemistry and molecular biology tools to probe physical and biological mechanisms for the synergistic activation of two TLRs. In this application, we study the enhanced activity and antibody response of two TLR agonists that are linked together. Previously, we showed that linking agonists of distinct TLRs (e.g. TLR2_TLR9) leads to increased activation. Vaccines adjuvanted with Dual_TLR agonists improve the breadth and intensity of antibody response. Moreover, these synergies are controlled by the linker-length and receptor identity implying control at the molecular level by physical phenomenon. Studying the mechanism of Dual_TLR agonists will result in fundamental understanding of signaling synergies within cells as well as an understanding of the mechanism that links cellular responses to antibody diversity mediated by TLR signaling. With this fundamental knowledge, it will be easier to apply the knowledge gained from viral vaccines to the designing new adjuvants.