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.

Public Health Relevance

The response of the immune system requires coordinated information to determine self from non- self. Just like in a musical composition, the right notes must be played at the right time. Currently, the mechanism of how the notes are discovered and how they translate to new actions is not well understood. By creating molecules that activate and stimulate the innate immune system, we will study how the system works and learn the mechanism behind how these responses are coordinated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AI124286-01
Application #
9108584
Study Section
Special Emphasis Panel (ZAI1-LGR-I (J1))
Program Officer
Lapham, Cheryl K
Project Start
2016-03-08
Project End
2021-02-28
Budget Start
2016-03-08
Budget End
2017-02-28
Support Year
1
Fiscal Year
2016
Total Cost
$525,953
Indirect Cost
$177,296
Name
University of California Irvine
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
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Moser, Brittany A; Esser-Kahn, Aaron P (2017) A Photoactivatable Innate Immune Receptor for Optogenetic Inflammation. ACS Chem Biol 12:347-350
Ryu, Keun Ah; Slowinska, Katarzyna; Moore, Troy et al. (2016) Immune Response Modulation of Conjugated Agonists with Changing Linker Length. ACS Chem Biol 11:3347-3352